Cannabinoid receptor ligands and uses thereof

ABSTRACT

Compounds of Formula (I) that act as cannabinoid receptor ligands and their uses in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals are described herein.

This application claims the benefit of U.S. Provisional Application Nos.60/464,918, filed on Apr. 23, 2003 and 60/540,048, filed on Jan. 29,2004, both of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to pyrazolo[4,3-d]pyrimidine andpyrazolo[3,4-c]pyridine compounds as cannabinoid receptor ligands, inparticular CB1 receptor antagonists, and uses thereof for treatingdiseases, conditions and/or disorders modulated by cannabinoid receptorantagonists.

BACKGROUND

Obesity is a major public health concern because of its increasingprevalence and associated health risks. Obesity and overweight aregenerally defined by body mass index (BMI), which is correlated withtotal body fat and estimates the relative risk of disease. BMI iscalculated by weight in kilograms divided by height in meters squared(kg/m²). Overweight is typically defined as a BMI of 25-29.9 kg/m², andobesity is typically defined as a BMI of 30 kg/m². See, e.g., NationalHeart, Lung, and Blood Institute, Clinical Guidelines on theIdentification, Evaluation, and Treatment of Overweight and Obesity inAdults, The Evidence Report, Washington, D.C.: U.S. Department of Healthand Human Services, NIH publication no. 98-4083 (1998).

The increase in obesity is of concern because of the excessive healthrisks associated with obesity, including coronary heart disease,strokes, hypertension, type 2 diabetes mellitus, dyslipidemia, sleepapnea, osteoarthritis, gall bladder disease, depression, and certainforms of cancer (e.g., endometrial, breast, prostate, and colon). Thenegative health consequences of obesity make it the second leading causeof preventable death in the United States and impart a significanteconomic and psychosocial effect on society. See, McGinnis M, Foege WH., “Actual Causes of Death in the United States,” JAMA, 270, 2207-12(1993).

Obesity is now recognized as a chronic disease that requires treatmentto reduce its associated health risks. Although weight loss is animportant treatment outcome, one of the main goals of obesity managementis to improve cardiovascular and metabolic values to reduceobesity-related morbidity and mortality. It has been shown that 5-10%loss of body weight can substantially improve metabolic values, such asblood glucose, blood pressure, and lipid concentrations. Hence, it isbelieved that a 5-10% intentional reduction in body weight may reducemorbidity and mortality.

Currently available prescription drugs for managing obesity generallyreduce weight by inducing satiety or decreasing dietary fat absorption.Satiety is achieved by increasing synaptic levels of norepinephrine,serotonin, or both. For example, stimulation of serotonin receptorsubtypes 1B, 1D, and 2C and 1- and 2-adrenergic receptors decreases foodintake by regulating satiety. See, Bray G A, “The New Era of DrugTreatment. Pharmacologic Treatment of Obesity: Symposium Overview,” ObesRes., 3(suppl 4), 415s-7s (1995). Adrenergic agents (e.g.,diethylpropion, benzphetamine, phendimetrazine, mazindol, andphentermine) act by modulating central norepinephrine and dopaminereceptors through the promotion of catecholamine release. Olderadrenergic weight-loss drugs (e.g., amphetamine, methamphetamine, andphenmetrazine), which strongly engage in dopamine pathways, are nolonger recommended because of the risk of their abuse. Fenfluramine anddexfenfluramine, both serotonergic agents used to regulate appetite, areno longer available for use.

More recently, CB1 cannabinoid receptor antagonists/inverse agonistshave been suggested as potential appetite suppressants. See, e.g.,Arnone, M., et al., “Selective Inhibition of Sucrose and Ethanol Intakeby SR141716, an Antagonist of Central Cannabinoid (CB1) Receptors,”Psychopharmacol, 132, 104-106 (1997); Colombo, G., et al., “AppetiteSuppression and Weight Loss after the Cannabinoid Antagonist SR141716,”Life Sci., 63, PL113-PL117 (1998); Simiand, J., et al., “SR141716, a CB1Cannabinoid Receptor Antagonist, Selectively Reduces Sweet Food Intakein Marmose,” Behav. Pharmacol., 9, 179-181 (1998); and Chaperon, F., etal., “Involvement of Central Cannabinoid (CB1) Receptors in theEstablishment of Place Conditioning in Rats,” Psychopharmacology, 135,324-332 (1998). For a review of cannabinoid CB1 and CB2 receptormodulators, see Pertwee, R. G., “Cannabinoid Receptor Ligands: Clinicaland Neuropharmacological Considerations, Relevant to Future DrugDiscovery and Development,” Exp. Opin. Invest. Drugs, 9(7), 1553-1571(2000).

Although investigations are on-going, there still exists a need for amore effective and safe therapeutic treatment for reducing or preventingweight-gain.

In addition to obesity, there also exists an unmet need for treatment ofalcohol abuse. Alcoholism affects approximately 10.9 million men and 4.4million women in the United States. Approximately 100,000 deaths peryear have been attributed to alcohol abuse or dependence. Health risksassociated with alcoholism include impaired motor control and decisionmaking, cancer, liver disease, birth defects, heart disease, drug/druginteractions, pancreatitis and interpersonal problems. Studies havesuggested that endogenous cannabinoid tone plays a critical role in thecontrol of ethanol intake. The endogenous CB1 receptor antagonistSR-141716A has been shown to block voluntary ethanol intake in rats andmice. See, Arnone, M., et al., “Selective Inhibition of Sucrose andEthanol Intake by SR141716, an Antagonist of Central Cannabinoid (CB1)Receptors,” Psychopharmacol, 132, 104-106 (1997). For a review, seeHungund, B. L and B. S. Basavarajappa, “Are Anandamide and CannabinoidReceptors involved in Ethanol Tolerance? A Review of the Evidence,”Alcohol & Alcoholism. 35(2) 126-133, 2000.

Current treatments for alcohol abuse or dependence generally suffer fromnon-compliance or potential hepatotoxicity; therefore, there is a highunmet need for more effective treatment of alcohol abuse/dependence.

SUMMARY

The present invention provides compounds of Formula (I) that act ascannabinoid receptor ligands (in particular, CB1 receptor antagonists)

wherein

A is N or C(R²), where R² is hydrogen, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl, or (C₁-C₄)alkoxy;

R⁰ is an optionally substituted heteroaryl or a substituted aryl(preferably, R⁰ is a substituted phenyl, more preferably a phenylsubstituted with one to three substituents independently selected fromthe group consisting of halo (preferably, chloro or fluoro),(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl (preferablyfluoro-substituted alkyl), and cyano, most preferably, R⁰ is2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or2,4-difluorophenyl);

R¹ is an optionally substituted heteroaryl or a substituted aryl(preferably, R¹ is a substituted phenyl, more preferably a phenylsubstituted with one to three substituents independently selected fromthe group consisting of halo (preferably, chloro or fluoro),(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl (preferablyfluoro-substituted alkyl), and cyano, most preferably, R¹ is4-chlorophenyl or 4-fluorophenyl);

R³ is hydrogen, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or(C₁-C₄)alkoxy;

R⁴ is

(i) a group having Formula (IA) or Formula (IB)

where R^(4a) is hydrogen or (C₁-C₃)alkyl;

-   -   R^(4b) and R^(4b′) are each independently hydrogen, cyano,        hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the        group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a partially or fully saturated carbocyclic        ring, where said moiety is optionally substituted with one or        more substituents,    -   or either R^(4b) or R^(4b′) taken together with R^(4e), R^(4e′),        R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an        ethylene bridge;    -   X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) and        R^(4c′) are each independently hydrogen, cyano, hydroxy, amino,        H₂NC(O)—, or a chemical moiety selected from the group        consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a 3-6 membered partially or fully saturated        carbocyclic ring, where said moiety is optionally substituted        with one or more substituents,    -   or either R⁴ or R^(4c′) taken together with R^(4e), R^(4e′),        R^(4f), or R^(4f′) forms a bond, a methylene bridge or an        ethylene bridge;    -   Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, where        R^(4d) and R^(4d′) are each independently hydrogen, cyano,        hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the        group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a 3-6 membered partially or fully saturated        carbocyclic ring, where said moiety is optionally substituted        with one or more substituents,    -   or R^(4d) and R^(4d′) taken together form a 3-6 membered        partially or fully saturated carbocyclic ring, 3-6 membered        partially or fully saturated heterocyclic ring, a 5-6 membered        lactone ring, or a 4-6 membered lactam ring, where said        carbocyclic ring, said heterocyclic ring, said lactone ring and        said lactam ring are optionally substituted with one or more        substituents and said lactone ring and said lactam ring        optionally contain an additional heteroatom selected from        oxygen, nitrogen or sulfur, or

Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents;

-   -   Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) and        R^(4e′) are each independently hydrogen, cyano, hydroxy, amino,        H₂NC(O)—, or a chemical moiety selected from the group        consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a 3-6 membered partially or fully saturated        carbocyclic ring, where said moiety is optionally substituted        with one or more substituents,    -   or either R^(4e) or R^(4e′) taken together with R^(4b), R^(4b′),        R^(4c), or R^(4c′) forms a bond, a methylene bridge or an        ethylene bridge; and    -   R^(4f) and R^(4f′) are each independently hydrogen, cyano,        hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the        group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a 3-6 membered partially or fully saturated        carbocyclic ring, where said moiety is optionally substituted        with one or more substituents,    -   or either R^(4f) or R^(4f′) taken together with R^(4b), R^(4b′),        R^(4c), or R^(4c′) forms a bond, a methylene bridge or an        ethylene bridge;

(ii) a group having Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl, or (C₁-C₄)alkyl,and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or an optionallysubstituted 4-6 membered partially or fully saturated heterocylic ringcontaining 1 to 2 heteroatoms independently selected from oxygen, sulfuror nitrogen,

or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6 membered lactone,4-6 membered lactam, or a 4-6 membered partially or fully saturatedheterocycle containing 1 to 2 heteroatoms independently selected fromoxygen, sulfur or nitrogen, where said lactone, said lactam and saidheterocycle are optionally substituted with one or more substituents;

(iii) an amino group having attached thereto at least one chemicalmoiety selected from the group consisting of (C₁-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; or

(iv) an (C₁-C₆)alkyl group having attached thereto at least one chemicalmoiety selected from the group consisting of hydroxy, (C₁-C₆)alkoxy,amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino (C₁-C₃)alkylsulfonyl,(C₁-C₃)alkylsulfamyl, di((C₁-C₃)alkyl)sulfamyl, acyloxy, a fully orpartially saturated heterocycle, and a fully or partially saturatedcarbocyclic ring, where said chemical moiety is optionally substitutedwith one or more substituents;

a pharmaceutically acceptable salt thereof, a prodrug of the compound orthe salt, or a solvate or hydrate of the compound, the salt or theprodrug.

In another embodiment of the present invention, a compound of Formula(II) is provided.

wherein

A is N or C(R²), where R² is hydrogen, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl, or (C₁-C₄)alkoxy;

R^(0a), R^(0b), R^(1a), and R^(1b) are each independently halo,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or cyano;

n and m are each independently 0, 1 or 2;

R³ is hydrogen, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or(C₁-C₄)alkoxy;

R⁴ is

(i) a group having Formula (IA) or Formula (IB)

where R^(4a) is hydrogen or (C₁-C₃)alkyl;

-   -   R^(4b) and R^(4b′) are each independently hydrogen, cyano,        hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the        group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a partially or fully saturated carbocyclic        ring, where the moiety is optionally substituted with one or        more substituents,    -   or either R^(4b) or R^(4b′) taken together with R^(4e), R^(4e′),        R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an        ethylene bridge;    -   X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) and        R^(4c′) are each independently hydrogen, cyano, hydroxy, amino,        H₂NC(O)—, or a chemical moiety selected from the group        consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a 3-6 membered partially or fully saturated        carbocyclic ring, where the moiety is optionally substituted        with one or more substituents,    -   or either R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′),        R^(4f), or R^(4f′) forms a bond, a methylene bridge or an        ethylene bridge;    -   Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, where        R^(4d) and R^(4d′) are each independently hydrogen, cyano,        hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the        group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a 3-6 membered partially or fully saturated        carbocyclic ring, where the moiety is optionally substituted        with one or more substituents,    -   or R^(4d) and R^(4d′) taken together form a 3-6 membered        partially or fully saturated carbocyclic ring, a 3-6 membered        partially or fully saturated heterocyclic ring, a 5-6 membered        lactone ring, or a 4-6 membered lactam ring, where said        carbocyclic ring, said heterocyclic ring, said lactone ring and        said lactam ring are optionally substituted with one or more        substituents and said lactone ring and said lactam ring        optionally contain an additional heteroatom selected from        oxygen, nitrogen or sulfur, or    -   Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or a chemical        moiety selected from the group consisting of (C₁-C₆)alkyl,        (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,        (C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,        (C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where the moiety is        optionally substituted with one or more substituents;    -   Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) and        R^(4e′) are each independently hydrogen, cyano, hydroxy, amino,        H₂NC(O)—, or a chemical moiety selected from the group        consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocyclic ring, and a 3-6 membered partially or fully        saturated carbocyclic ring, where the moiety is optionally        substituted with one or more substituents,    -   or either R^(4e) or R^(4e′) taken together with R^(4b), R^(4b′),        R^(4c), or R^(4c′) forms a bond, a methylene bridge or an        ethylene bridge; and    -   R^(4f) and R^(4f′) are each independently hydrogen, cyano,        hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the        group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,        (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,        ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,        di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,        aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,        heteroaryl, a 3-6 membered partially or fully saturated        heterocycle, and a 3-6 membered partially or fully saturated        carbocyclic ring, where the moiety is optionally substituted        with one or more substituents,    -   or either R^(4f) or R^(4f′) taken together with R^(4b), R^(4b′),        R^(4c), or R^(4c′) forms a bond, a methylene bridge or an        ethylene bridge;

(ii) a group having Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl, or (C₁-C₄)alkyl,and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or an optionallysubstituted 4-6 membered partially or fully saturated heterocylic ringcontaining 1 to 2 heteroatoms independently selected from oxygen, sulfuror nitrogen,

or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6 membered lactone,4-6 membered lactam, or a 4-6 membered partially or fully saturatedheterocycle containing 1 to 2 heteroatoms independently selected fromoxygen, sulfur or nitrogen, where said lactone, said lactam and saidheterocycle are optionally substituted with one or more substituents;

(iii) an amino group having attached thereto at least one chemicalmoiety selected from the group consisting of (C₁-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; or

(iv) an (C₁-C₆)alkyl group having attached thereto at least one chemicalmoiety selected from the group consisting of hydroxy, (C₁-C₆)alkoxy,amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino (C₁-C₃)alkylsulfonyl,(C₁-C₃)alkylsulfamyl, di((C₁-C₃)alkyl)sulfamyl, acyloxy, a fully orpartially saturated heterocycle, and a fully or partially saturatedcarbocyclic ring, where said chemical moiety is optionally substitutedwith one or more substituents;

a pharmaceutically acceptable salt thereof, a prodrug of the compound orthe salt, or a solvate or hydrate of the compound, the salt or theprodrug.

A preferred compound of the present invention is a compound of Formula(I) or (II) where R⁴ is a group of Formula (IA). Preferably, R^(4b) andR^(4b′) are each independently hydrogen, H₂NC(O)—, or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a partially or fully saturated 3-6 memberedheterocycle, and a partially or fully saturated carbocyclic ring, wherethe moiety is optionally substituted, or R^(4b) or R^(4b′) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge;

X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) is hydrogen,cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from thegroup consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted, or R^(4c) taken together with R^(4e), R^(4e′)R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an ethylenebridge, and R^(4c′) is hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted, or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge, or an ethylene bridge;

Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted, and R^(4d′) is hydrogen, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a partially or fully saturated 3-6 memberedheterocycle, and a partially or fully saturated carbocyclic ring, wherethe moiety is optionally substituted, or R^(4d) and R^(4d′) takentogether form a partially or fully saturated, 3-6 membered heterocyclicring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherethe heterocyclic ring, the lactone ring and the lactam ring areoptionally substituted and the lactone ring and the lactam ringoptionally contain an additional heteroatom selected from oxygen,nitrogen or sulfur, or

Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted;

Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted, or R^(4e) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge, or an ethylenebridge, and R^(4e′) is hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted, or R^(4e), taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge, or an ethylene bridge; and

R^(4f) and R^(4f′) are each independently hydrogen, H₂NC(O)—, or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturated3-6 membered heterocycle, and a partially or fully saturated carbocyclicring, where the moiety is optionally substituted, or R^(4f) or R^(4f′)taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge;

a pharmaceutically acceptable salt thereof, a prodrug of the compound orthe salt, or a solvate or hydrate of the compound, the salt or theprodrug.

Preferably, R^(4b) is hydrogen, an optionally substituted (C₁-C₃)alkyl,or taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond,a methylene bridge, or an ethylene bridge; R^(4b′) is hydrogen, anoptionally substituted (C₁-C₃)alkyl, or taken together with R^(4e),R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, or anethylene bridge; R^(4f) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′)forms a bond, a methylene bridge, or an ethylene bridge; and R^(4f) ishydrogen, an optionally substituted (C₁-C₃)alkyl, or taken together withR^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, oran ethylene bridge, and even more preferably, R^(4b), R^(4b′), R^(4f),and R^(4f′) are all hydrogen.

When Y is —NR^(4d″)—, then R^(4d″) is preferably a hydrogen or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted (more preferably,R^(4d″) is a hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, (C₁-C₆)alkyl-O—C(O)—, and heteroaryl,where the moiety is optionally substituted (preferably the(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, and (C₁-C₆)alkyl-O—C(O)— areoptionally substituted with 1-3 fluorines, and the heteroaryl isoptionally substituted with 1 to 2 substituents independently selectedfrom the group consisting of chloro, fluoro, (C₁-C₃)alkoxy,(C₁-C₃)alkyl, and fluoro-substituted (C₁-C₃)alkyl);

X is —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are eachindependently hydrogen, H₂NC(O)—, an optionally substituted(C₁-C₈)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, oreither R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge or an ethylene bridge; and

Z is —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are eachindependently hydrogen, H₂NC(O)—, an optionally substituted(C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, oreither R^(4e) or R^(4c′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge.

When Y is —C(R^(4d))(R^(4d′))—, then R^(4d) is hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a partially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted (preferably, R^(4d) is amino, (C₁-C₆)alkylamino,di(C₁-C₄)alkylamino, (C₃-C₆)cycloalkylamino, acylamino,aryl(C₁-C₄)alkylamino-, or heteroaryl(C₁-C₄)alkylamino, more preferably,R^(4d) is amino, (C₁-C₆)alkylamino, di(C₁-C₄)alkylamino,(C₃-C₆)cycloalkylamino), and

R^(4d′) is hydrogen, H₂NC(O)—, or a chemical moiety selected from thegroup consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted (preferably, R^(4d′) is (C₁-C₆)alkyl, H₂NC(O)—,(C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, or aryl, morepreferably, R^(4d′) is H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—, or((C₁-C₄)alkyl)₂N—C(O)—),

or R^(4d) and R^(4d′) taken together form a partially or fullysaturated, 3-6 membered heterocyclic ring, a 5-6 membered lactone ring,or a 4-6 membered lactam ring, where the heterocyclic ring, the lactonering and the lactam ring are optionally substituted and the lactone ringand the lactam ring optionally contain an additional heteroatom selectedfrom oxygen, nitrogen or sulfur;

X is a bond or —C(R)(R^(4c′))—, where R^(4c) and R^(4c′) are eachhydrogen; and Z is a bond or —C(R^(4e))(R^(4e′))—, where R^(4e) andR^(4e′) are each hydrogen.

Preferred compounds include:3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-methylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-cyclopentyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine;5-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester;5-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-[5-(propane-2-sulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-[5-(2,2,2-trifluoroethanesulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-pyrazolo[4,3-d]pyrimidine;5-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-sulfonicacid dimethylamide;4-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-piperazine-1-sulfonicacid dimethylamide;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-ethanesulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-(2,2,2-trifluoroethane)sulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-methanesulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-(propane-2-sulfonyl)piperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;and 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-methylpiperazin-1-yl)-2H-pyrazolo[3,4-c]pyridine; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.

In another preferred embodiment, a compound of Formula (I) or (II) isprovided where Y is —C(R^(4d))(R^(4d′))—, R^(4b), R^(4b′), R^(4f), andR^(4f′) are all hydrogen; R^(4d) is hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents; and R^(4d′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents.

In this embodiment, X is preferably —C(R^(4c))(R^(4c′))—, where R^(4c),and R^(4c′) are each independently hydrogen or an optionally substituted(C₁-C₆)alkyl, or either R^(4c) or R^(4c′) taken together with R^(4e) orR^(4e′) forms a bond, a methylene bridge or an ethylene bridge(preferably, R^(4c) and R^(4c′) are each hydrogen or either R^(4c) orR^(4c′) taken together with R^(4e), or R^(4e′) forms a bond); and Z ispreferably —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are eachindependently hydrogen or an optionally substituted (C₁-C₆)alkyl, oreither R^(4e) or R^(4e′) taken together with R^(4c) or R^(4c′) forms abond, a methylene bridge or an ethylene bridge (preferably, R^(4e) andR^(4e′) are each hydrogen or either R^(4e) or R^(4e′) taken togetherwith R^(4c) or R^(4c′) forms a bond). Preferably, R^(4d) is amino,(C₁-C₆)alkylamino, di(C₁-C₄)alkylamino, azetidinyl, piperidinyl,pyrrolidinyl, morpholinyl, (C₃-C₆)cycloalkylamino, acylamino,aryl(C₁-C₄)alkylamino-, or heteroaryl(C₁-C₄)alkylamino-; and R^(4d′) is(C₁-C₆)alkyl, H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—,or aryl. More preferably, R^(4d) is amino, (C₁-C₆)alkylamino,di(C₁-C₄)alkylamino, (C₃-C₆)cycloalkylamino, piperidinyl, pyrrolidinyl,or morpholinyl; and R^(4d′) is H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—, or((C₁-C₄)alkyl)₂N—C(O)—.

In yet another preferred embodiment, a compound of Formula (I) or (II)is provided where Y is C(R^(4d))(R^(4d′))—, R^(4b), R^(4b′), R^(4f), andR^(4f′) are all hydrogen; and R^(4d) and R^(4d′) taken together form apartially or fully saturated 3-6 membered heterocyclic ring, a 5-6membered lactone ring, or a 4-6 membered lactam ring, where theheterocyclic ring, the lactone ring and the lactam ring are optionallysubstituted with one or more substituents and the lactone ring or thelactam ring optionally contains an additional heteroatom selected fromoxygen, nitrogen or sulfur (preferably, R^(4d) and R^(4d′) takentogether form a 5-6 membered lactam ring, where the lactam ring isoptionally substituted and optionally contains an additional heteroatomselected from nitrogen or oxygen). In this embodiment, X is preferably abond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) areeach independently hydrogen or an optionally substituted (C₁-C₆)alkyl,or either R^(4c) or R^(4c′) taken together with R^(4e) or R^(4e′) formsa bond, a methylene bridge or an ethylene bridge (more preferably, X isa bond or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are eachhydrogen); and Z is preferably a bond, —CH₂CH₂— or

—C(R^(4e))(R^(4e′)), where R^(4c) and R^(4c′) are each independentlyhydrogen or an optionally substituted (C₁-C₆)alkyl, or either R^(4e) orR^(4e′) taken together with R^(4c) or R^(4c′) forms a bond, a methylenebridge or an ethylene bridge (more preferably, Z is a bond or—C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are each hydrogen).

Preferred compounds include:1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-ethylaminoazetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-methylaminoazetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-(2-propylamino)azetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-pyrrolidin-1-yl-8-aza-bicyclo[3.2.1]octane-3-carboxylicacid amide;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,3′]bipyrrolidinyl-3′-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-morpholin-4-yl-pyrrolidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropylaminopyrrolidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide; and1′-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide a pharmaceutically acceptable salt thereof or a solvate orhydrate of said compound or said salt.

More preferred compounds include:1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropylaminopyrrolidine-3-carboxylicacid amide; and1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide; a pharmaceutically acceptable salt thereof or a solvate orhydrate of said compound or said salt.

Another set of preferred compounds include:1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-ethylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-isopropylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-sec-butylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpiperidin-4-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-ethyl-8-azabicyclo[3.2.1]octan-3-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-sec-butyl-8-azabicyclo[3.2.1]octan-3-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropyl-8-azabicyclo[3.2.1]octan-3-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isobutyl-pyrrolidin-3-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropyl-pyrrolidin-3-ol;{8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-ethyl-amine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(3-pyrrolidin-1-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-2H-pyrazolo[4,3-d]pyrimidine;7-(3-bromo-8-azabicyclo[3.2.1]oct-8-yl)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;7-(3-bromo-8-azabicyclo[3.2.1]oct-8-yl)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-methylpiperidin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(3-hydroxypiperidin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-(3-methoxyphenyl)-piperidine-4-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidine-4-carbonitrile;1-{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidin-4-yl}-propan-1-one;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,3,5,6-tetrahydro-1H-[4,4′]bipyridinyl-4-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,3,5,6-tetrahydro-1H-[2,4′]bipyridinyl-4-carbonitrile;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidin-4-yl}-morpholin-4-yl-methanone;benzyl-{8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-methylcarbamicacid tert-butyl ester;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester;N-{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-N-methylacetamide;and{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-dimethylamine;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.

Yet another set of preferred compounds include:2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-5-methyl-2,5,7-triaza-spiro[3,4]octan-8-one;8-[3-(4-chloro-phenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-isopropyl-1,3,8-triaza-spiro[4,5]decan-4-one;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[(5-methoxy)tetrahydronaphthalene-1,4′-piperidine];3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[(6-methoxy)tetrahydronaphthalene-1,4′-piperidine];and3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[indane-1,4′-piperidine];a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

Another preferred compound of the present invention is a compound ofFormula (I) or (II) where R⁴ is a group of Formula (IB) where R^(4a) isas defined above, R^(4b) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—,or a chemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a partially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents,

R^(4b′) is hydrogen, H₂NC(O)—, or a chemical moiety selected from thegroup consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents,

or R^(4b) or R^(4b′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge, or an ethylene bridge;

X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) is hydrogen,cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from thegroup consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted with one or more substituents, or R^(4c) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4c′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturated3-6 membered heterocycle, and a partially or fully saturated carbocyclicring, where the moiety is optionally substituted with one or moresubstituents, or R^(4c) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge, or an ethylene bridge(preferably, X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c)and R^(4c′) are each independently hydrogen or (C₁-C₆)alkyl);

Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted with one or more substituents, and R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a partially or fully saturated, 3-6 membered heterocyclicring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherethe heterocyclic ring, the lactone ring and the lactam ring areoptionally substituted with one or more substituents and the lactonering and the lactam ring optionally contain an additional heteroatomselected from oxygen, nitrogen or sulfur, or

Y is —NR^(4d″), where R^(4d″) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted with one or moresubstituents (preferably, Y is —NR^(4d″)—, where R^(4d″) is a hydrogenor a chemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted with one or moresubstituents);

Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted with one or more substituents, or R^(4e) takentogether with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4e) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturated3-6 membered heterocycle, and a partially or fully saturated carbocyclicring, where the moiety is optionally substituted with one or moresubstituents, or R^(4e′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge, or an ethylene bridge(preferably, Z is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c)and R^(4c′) are each independently hydrogen or (C₁-C₆)alkyl);

R^(4f) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a partially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents; and

R^(4f′) is hydrogen, H₂NC(O)—, or a chemical moiety selected from thegroup consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents,

or R^(4f) or R^(4f′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge, or an ethylene bridge;

a pharmaceutically acceptable salt thereof, a prodrug of the compound orthe salt, or a solvate or hydrate of the compound, the salt or theprodrug.

Preferred compounds include:7-(1-benzhydrylazetidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;and7-(1-benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

Yet another preferred compound of the present invention is a compound ofFormula (I) or (II) where R⁴ is a group of Formula (IC), where R⁵ and R⁶are each independently hydrogen, aryl, or (C₁-C₄)alkyl, and R⁷ is anoptionally substituted (C₁-C₄)alkyl-, or an optionally substituted 4-6membered partially or fully saturated heterocylic ring containing 1 to 2heteroatoms independently selected from oxygen, sulfur or nitrogen, orR⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6 membered lactone, 4-6membered lactam, or a 4-6 membered partially or fully saturatedheterocycle containing 1 to 2 heteroatoms independently selected fromoxygen, sulfur or nitrogen, where said lactone, said lactam and saidheterocycle are optionally substituted with one or more substituents; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.

Preferred compounds include:2-(2-chlorophenyl)-7-isopropoxy-3-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-chloro-4-methylphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-3-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-chlorophenyl)-3-(4-methoxyphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-bromophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;2-(2-bromophenyl)-3-(4-methoxyphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;2-[3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methylpyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile;2-(2-bromophenyl)-7-(2,2-difluoropropoxy)-3-(4-methoxyphenyl)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-bromophenyl)-2-(2-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;2-(2-chlorophenyl)-7-(2,2-difluoropropoxy)-3-(4-methoxyphenyl)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-methoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-ethoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-propoxy-2H-pyrazolo[4,3-d]pyrimidine;7-butoxy-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-isopropyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-ethoxy-5-trifluoromethyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2,2-trifluoroethoxy)-5-trifluoromethyl-2H-pyrazolo[4,3-d]pyrimidine;and3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2-difluorobutoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;

a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

Yet another preferred compound of the present invention is a compound ofFormula (I) or (II) wherein R⁴ is an amino group having attached theretoat least one chemical moiety selected from the group consisting of(C₁-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially or fullysaturated carbocyclic ring, hydroxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, heteroaryl(C₁-C₃)alkyl, and a fully orpartially saturated heterocycle, where said chemical moiety isoptionally substituted with one or more substituents.

Preferred compounds include:N-4-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-N,N-diethylpentane-1,4-diamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-2-morpholin-4-yl-ethyl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-2-yl-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methylpyridin-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methoxypyridin-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amine;(6-azetidin-1-yl-pyridin-3-yl)-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-2-ylmethylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methyl-pyridin-2-ylmethyl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-3-ylmethylamine;[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclohexylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(4-methyl-cyclohexyl)amine;adamantan-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(3-methylcyclohexyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentanecarboxylicacid ethyl ester;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclohexanol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2,6-dimethylcyclohexyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cycloheptylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cyclobutylamine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-2-methylpropane-1,3-diol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-1-phenylethyl)amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentyl}methanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-2-methylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,1-dimethylpropyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-3-phenylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-indan-2-ylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,2,3,4-tetrahydronaphthalen-1-yl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-1-pyrrolidin-1-ylpropan-1-one;4-{2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]propyl}phenol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-p-tolylethyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2-phenylcyclopropyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]indan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2-morpholin-4-yl-ethyl)amine;(1H-Benzoimidazol-2-ylmethyl)-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]propan-2-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2,2,2-trifluoroethyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclopropylmethylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;and3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[3,4-c]pyridine;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

More preferred compounds include:[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclohexylamine;adamantan-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclohexanol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cyclobutylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-1-phenylethyl)amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentyl}methanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-3-phenylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-indan-2-ylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;and2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]indan-1-ol;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

Another aspect of the present invention comprises the followingintermediates which may be used in the preparation of the compounds ofFormula (I) and (II).

wherein R⁰, R¹, R², R³ are as defined above; R is an alkyl group(preferably, a (C₁-C₄)alkyl, more preferably, an ethyl); Pg is anamino-protecting group; and L is a leaving group.

Some of the compounds described herein contain at least one chiralcenter; consequently, those skilled in the art will appreciate that allstereoisomers (e.g., enantiomers and diasteroisomers) of the compoundsillustrated and discussed herein are within the scope of the presentinvention. In addition, tautomeric forms of the compounds are alsowithin the scope of the present invention. Those skilled in the art willrecognize that chemical moieties such as an alpha-amino ether or analpha-chloro amine may be too unstable to isolate; therefore, suchmoieties do not form a part of this invention.

Compounds of the present invention have been shown to be usefulcannabinoid receptor ligands (in particular, CB1 receptor antagonists).Accordingly, another aspect of the present invention is a pharmaceuticalcomposition that comprises (1) a compound of the present invention, and(2) a pharmaceutically acceptable excipient, diluent, or carrier.Preferably, the composition comprises a therapeutically effective amountof a compound of the present invention. The composition may also containat least one additional pharmaceutical agent (described herein).Preferred agents include nicotine receptor partial agonists, opioidantagonists (e.g., naltrexone and nalmefene), dopaminergic agents (e.g.,apomorphine), attention deficit disorder (ADD including attentiondeficit hyperactivity disorder (ADHD)) agents (e.g., Ritalin™,Strattera™, Concerta™ and Adderall™), and anti-obesity agents (describedherein below).

In yet another embodiment of the present invention, a method fortreating a disease, condition or disorder modulated by a cannabinoidreceptor (preferably, a CB1 receptor) antagonists in animals thatincludes the step of administering to an animal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention (or a pharmaceutical composition thereof).

Diseases, conditions, and/or disorders modulated by cannabinoid receptorantagonists include eating disorders (e.g., binge eating disorder,anorexia, and bulimia), weight loss or control (e.g., reduction incalorie or food intake, and/or appetite suppression), obesity,depression, atypical depression, bipolar disorders, psychoses,schizophrenia, behavioral addictions, suppression of reward-relatedbehaviors (e.g., conditioned place avoidance, such as suppression ofcocaine- and morphine-induced conditioned place preference), substanceabuse, addictive disorders, impulsivity, alcoholism (e.g., alcoholabuse, addiction and/or dependence including treatment for abstinence,craving reduction and relapse prevention of alcohol intake), tobaccoabuse (e.g., smoking addiction, cessation and/or dependence includingtreatment for craving reduction and relapse prevention of tobaccosmoking), dementia (including memory loss, Alzheimer's disease, dementiaof aging, vascular dementia, mild cognitive impairment, age-relatedcognitive decline, and mild neurocognitive disorder), sexual dysfunctionin males (e.g., erectile difficulty), seizure disorders, epilepsy,inflammation, gastrointestinal disorders (e.g., dysfunction ofgastrointestinal motility or intestinal propulsion), attention deficitdisorder (ADD/ADHD), Parkinson's disease, and type II diabetes. In apreferred embodiment, the method is used in the treatment of weightloss, obesity, bulimia, ADD/ADHD, Parkinson's disease, dementia,alcoholism, and/or tobacco abuse.

Compounds of the present invention may be administered in combinationwith other pharmaceutical agents. Preferred pharmaceutical agentsinclude nicotine receptor partial agonists, opioid antagonists (e.g.,naltrexone (including naltrexone depot), antabuse, and nalmefene),dopaminergic agents (e.g., apomorphine), ADD/ADHD agents (e.g.,methylphenidate hydrochloride (e.g., Ritalin™ and Concerta™),atomoxetine (e.g., Strattera™), and amphetamines (e.g., Adderall™)) andanti-obesity agents, such as apo-B/MTP inhibitors, 11β-hydroxy steroiddehydrogenase-1 (11β-HSD type 1) inhibitors, peptide YY₃₋₃₆ or analogsthereof, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors,sympathomimetic agents, β₃ adrenergic receptor agonists, dopaminereceptor agonists, melanocyte-stimulating hormone receptor analogs,5-HT2c receptor agonists, melanin concentrating hormone receptorantagonists, leptin, leptin analogs, leptin receptor agonists, galaninreceptor antagonists, lipase inhibitors, bombesin receptor agonists,neuropeptide-Y receptor antagonists (e.g., NPY-5 receptor antagonistssuch as those described herein below), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andthe like.

The combination therapy may be administered as (a) a singlepharmaceutical composition which comprises a compound of the presentinvention, at least one additional pharmaceutical agent described hereinand a pharmaceutically acceptable excipient, diluent, or carrier; or (b)two separate pharmaceutical compositions comprising (i) a firstcomposition comprising a compound of the present invention and apharmaceutically acceptable excipient, diluent, or carrier, and (ii) asecond composition comprising at least one additional pharmaceuticalagent described herein and a pharmaceutically acceptable excipient,diluent, or carrier. The pharmaceutical compositions may be administeredsimultaneously or sequentially and in any order.

In yet another aspect of the present invention, a pharmaceutical kit isprovided for use by a consumer to treat diseases, conditions ordisorders modulated by cannabinoid receptor antagonists in an animal.The kit comprises a) a suitable dosage form comprising a compound of thepresent invention; and b) instructions describing a method of using thedosage form to treat diseases, conditions or disorders that aremodulated by cannabinoid receptor (in particular, the CB1 receptor)antagonists.

In yet another embodiment of the present invention is a pharmaceuticalkit comprising: a) a first dosage form comprising (i) a compound of thepresent invention and (ii) a pharmaceutically acceptable carrier,excipient or diluent; b) a second dosage form comprising (i) anadditional pharmaceutical agent described herein, and (ii) apharmaceutically acceptable carrier, excipient or diluent; and c) acontainer.

Definitions

As used herein, the term “alkyl” refers to a hydrocarbon radical of thegeneral formula C_(n)H_(2n+1). The alkane radical may be straight orbranched. For example, the term “(C₁-C₆)alkyl” refers to a monovalent,straight, or branched aliphatic group containing 1 to 6 carbon atoms(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl(e.g., alkanoyl), alkylamino, dialkylamino, and alkylthio group have thesame definition as above. When indicated as being “optionallysubstituted”, the alkane radical or alkyl moiety may be unsubstituted orsubstituted with one or more substituents (generally, one to threesubstituents except in the case of halogen substituents such asperchloro or perfluoroalkyls) independently selected from the group ofsubstituents listed below in the definition for “substituted.”“Halo-substituted alkyl” refers to an alkyl group substituted with oneor more halogen atoms (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, perfluoroethyl, and the like). When substituted, thealkane radicals or alkyl moieties are preferably substituted with 1 to 3fluoro substituents, or 1 or 2 substituents independently selected from(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to6-membered heterocycle, chloro, cyano, hydroxy, (C₁-C₃)alkoxy, aryloxy,amino, (C₁-C₆)alkyl amino, di-(C₁-C₄)alkyl amino, aminocarboxylate(i.e., (C₁-C₃)alkyl-O—C(O)—NH—), hydroxy(C₂-C₃)alkylamino, or keto(oxo), and more preferably, 1 to 3 fluoro groups, or 1 substituentselected from (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, (C₆)aryl,6-membered-heteroaryl, 3- to 6-membered heterocycle, (C₁-C₃)alkoxy,(C₁-C₄)alkyl amino or di-(C₁-C₂)alkyl amino. When a carbon atom hasattached thereto geminal alkyl groups, then the alkyls may be takentogether to form a carbocyclic ring. For example, a carbon having twogeminal methyl groups would be equivalent to a cyclopropyl group.

The terms “partially or fully saturated carbocyclic ring” (also referredto as “partially or fully saturated cycloalkyl”) refers to nonaromaticrings that are either partially or fully hydrogenated and may exist as asingle ring, bicyclic ring or a spiral ring. Unless specified otherwise,the carbocyclic ring is generally a 3- to 8-membered ring. For example,partially or fully saturated carbocyclic rings (or cycloalkyl) includegroups such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclpentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, norbornyl (bicyclo[2.2.1]heptyl), norbornenyl,bicyclo[2.2.2]octyl, and the like. When designated as being “optionallysubstituted”, the partially saturated or fully saturated cycloalkylgroup may be unsubstituted or substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted.”A substituted carbocyclic ring also includes groups wherein thecarbocyclic ring is fused to a phenyl ring (e.g., indanyl). Thecarbocyclic group may be attached to the chemical entity or moiety byany one of the carbon atoms within the carbocyclic ring system. Whensubstituted, the carbocyclic group is preferably substituted with 1 or 2substituents independently selected from (C₁-C₃)alkyl, (C₂-C₃)alkenyl,(C₁-C₆)alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle,chloro, fluoro, cyano, hydroxy, (C₁-C₃)alkoxy, aryloxy, amino,(C₁-C₆)alkyl amino, di-(C₁-C₄)alkyl amino, aminocarboxylate (i.e.,(C₁-C₃)alkyl-O—C(O)—NH—), hydroxy(C₂-C₃)alkylamino, or keto (oxo), andmore preferably 1 or 2 from substituents independently selected from(C₁-C₂)alkyl, 3- to 6-membered heterocycle, fluoro, (C₁-C₃)alkoxy,(C₁-C₄)alkyl amino or di-(C₁-C₂)alkyl amino. Similarly, any cycloalkylportion of a group (e.g., cycloalkylalkyl, cycloalkylamino, etc.) hasthe same definition as above.

The term “partially saturated or fully saturated heterocyclic ring”(also referred to as “partially saturated or fully saturatedheterocycle”) refers to nonaromatic rings that are either partially orfully hydrogenated and may exist as a single ring, bicyclic ring or aspiral ring. Unless specified otherwise, the heterocyclic ring isgenerally a 3- to 6-membered ring containing 1 to 3 heteroatoms(preferably 1 or 2 heteroatoms) independently selected from sulfur,oxygen and/or nitrogen. Partially saturated or fully saturatedheterocyclic rings include groups such as epoxy, aziridinyl,tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl,N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, piperidinyl,piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl,oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, and the like. When indicated as being“optionally substituted”, the partially saturated or fully saturatedheterocycle group may be unsubstiuted or substituted with one or moresubstituents (typically, one to three substituents) independentlyselected from the group of substituents listed below in the definitionfor “substituted.” A substituted heterocyclic ring includes groupswherein the heterocyclic ring is fused to an aryl or heteroaryl ring(e.g., 2,3-dihydrobenzofuranyl, 2,3-dihydroindolyl,2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, etc.). Whensubstituted, the heterocycle group is preferably substituted with 1 or 2substituents independently selected from (C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₄)alkenyl, aryl, heteroaryl, 3- to 6-memberedheterocycle, chloro, fluoro, cyano, hydroxy, (C₁-C₃)alkoxy, aryloxy,amino, (C₁-C₆)alkyl amino, di-(C₁-C₃)alkyl amino, aminocarboxylate(i.e., (C₁-C₃)alkyl-O—C(O)—NH—), or keto (oxo), and more preferably with1 or 2 substituents independently selected from (C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, (C₆)aryl, 6-membered-heteroaryl, 3- to 6-memberedheterocycle, or fluoro. The heterocyclic group may be attached to thechemical entity or moiety by any one of the ring atoms within theheterocyclic ring system. Similarly, any heterocycle portion of a group(e.g., heterocycle-substituted alkyl, heterocycle carbonyl, etc.) hasthe same definition as above.

The term “aryl” or “aromatic carbocyclic ring” refers to aromaticmoieties having a single (e.g., phenyl) or a fused ring system (e.g.,naphthalene, anthracene, phenanthrene, etc.). A typical aryl group is a6- to 10-membered aromatic carbocyclic ring(s). When indicated as being“optionally substituted”, the aryl groups may be unsubstituted orsubstituted with one or more substituents (preferably no more than threesubstituents) independently selected from the group of substituentslisted below in the definition for “substituted.” Substituted arylgroups include a chain of aromatic moieties (e.g., biphenyl, terphenyl,phenylnaphthalyl, etc.). When substituted, the aromatic moieties arepreferably substituted with 1 or 2 substituents independently selectedfrom (C₁-C₄)alkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to 6-memberedheterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C₁-C₄)alkoxy,aryloxy, amino, (C₁-C₆)alkyl amino, di-(C₁-C₃)alkyl amino, oraminocarboxylate (i.e., (C₁-C₃)alkyl-O—C(O)—NH—), and more preferably, 1or 2 substituents independently selected from (C₁-C₄)alkyl, chloro,fluoro, cyano, hydroxy, or (C₁-C₄)alkoxy. The aryl group may be attachedto the chemical entity or moiety by any one of the carbon atoms withinthe aromatic ring system. Similarly, the aryl portion (i.e., aromaticmoiety) of an aroyl or aroyloxy (i.e., (aryl)-C(O)—O—) has the samedefinition as above.

The term “heteroaryl” or “heteroaromatic ring” refers to aromaticmoieties containing at least one heteratom (e.g., oxygen, sulfur,nitrogen or combinations thereof) within a 5- to 10-membered aromaticring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl,thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl,triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl,quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, etc.). Theheteroaromatic moiety may consist of a single or fused ring system. Atypical single heteroaryl ring is a 5- to 6-membered ring containing oneto three heteroatoms independently selected from oxygen, sulfur andnitrogen and a typical fused heteroaryl ring system is a 9- to10-membered ring system containing one to four heteroatoms independentlyselected from oxygen, sulfur and nitrogen. When indicated as being“optionally substituted”, the heteroaryl groups may be unsubstituted orsubstituted with one or more substituents (preferably no more than threesubstituents) independently selected from the group of substituentslisted below in the definition for “substituted.” When substituted, theheteroaromatic moieties are preferably substituted with 1 or 2substituents independently selected from (C₁-C₄)alkyl, (C₂-C₃)alkenyl,aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro,iodo, cyano, hydroxy, (C₁-C₄)alkoxy, aryloxy, amino, (C₁-C₆)alkyl amino,di-(C₁-C₃)alkyl amino, or aminocarboxylate (i.e.,(C₁-C₃)alkyl-O—C(O)—NH—), and more preferably, 1 or 2 substituentsindependently selected from (C₁-C₄)alkyl, chloro, fluoro, cyano,hydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl amino or di-(C₁-C₂)alkyl amino. Theheteroaryl group may be attached to the chemical entity or moiety by anyone of the atoms within the aromatic ring system (e.g., imidazol-1-yl,imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, pyrid-5-yl, or pyrid-6-yl). Similarly, the heteroarylportion (i.e., heteroaromatic moiety) of a heteroaroyl or heteroaroyloxy(i.e., (heteroaryl)-C(O)—O—) has the same definition as above.

The term “acyl” refers to hydrogen, alkyl, partially saturated or fullysaturated cycloalkyl, partially saturated or fully saturatedheterocycle, aryl, and heteroaryl substituted carbonyl groups. Forexample, acyl includes groups such as (C₁-C₆)alkanoyl (e.g., formyl,acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitionsabove. When indicated as being “optionally substituted”, the acyl groupmay be unsubstituted or optionally substituted with one or moresubstituents (typically, one to three substituents) independentlyselected from the group of substituents listed below in the definitionfor “substituted” or the alkyl, cycloalkyl, heterocycle, aryl andheteroaryl portion of the acyl group may be substituted as describedabove in the preferred and more preferred list of substituents,respectively.

The term “substituted” specifically envisions and allows for one or moresubstitutions that are common in the art. However, it is generallyunderstood by those skilled in the art that the substituents should beselected so as to not adversely affect the pharmacologicalcharacteristics of the compound or adversely interfere with the use ofthe medicament. Suitable substituents for any of the groups definedabove include (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, halo(e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (C₁-C₆)alkoxy,aryloxy, sulfhydryl (mercapto), (C₁-C₆)alkylthio, arylthio, amino, mono-or di-(C₁-C₆)alkyl amino, quaternary ammonium salts, amino(C₁-C₆)alkoxy,aminocarboxylate (i.e., (C₁-C₆)alkyl-O—C(O)—NH—),hydroxy(C₂-C₆)alkylamino, amino(C₁-C₆)alkylthio, cyanoamino, nitro,(C₁-C₆)carbamyl, keto (oxo), acyl, (C₁-C₆)alkyl-CO₂—, glycolyl, glycyl,hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thio(C₁-C₆)alkyl-C(O)—,thio(C₁-C₆)alkyl-CO₂—, and combinations thereof. In the case ofsubstituted combinations, such as “substituted aryl(C₁-C₆)alkyl”, eitherthe aryl or the alkyl group may be substituted, or both the aryl and thealkyl groups may be substituted with one or more substituents(typically, one to three substituents except in the case of perhalosubstitutions). An aryl or heteroaryl substituted carbocyclic orheterocyclic group may be a fused ring (e.g., indanyl,dihydrobenzofuranyl, dihydroindolyl, etc.).

The term “solvate” refers to a molecular complex of a compoundrepresented by Formula (I) or (II) (including prodrugs andpharmaceutically acceptable salts thereof) with one or more solventmolecules. Such solvent molecules are those commonly used in thepharmaceutical art, which are known to be innocuous to the recipient,e.g., water, ethanol, and the like. The term “hydrate” refers to thecomplex where the solvent molecule is water.

The term “protecting group” or “Pg” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein.

The term “animal” refers to humans (male or female), companion animals(e.g., dogs, cats and horses), food-source animals, zoo animals, marineanimals, birds and other similar animal species. “Edible animals” refersto food-source animals such as cows, pigs, sheep and poultry.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “treating”, “treat”, or “treatment” embrace both preventative,i.e., prophylactic, and palliative treatment.

The terms “modulated by a cannabinoid receptor” or “modulation of acannabinoid receptor” refers to the activation or deactivation of acannabinoid receptor. For example, a ligand may act as an agonist,partial agonist, inverse agonist, antagonist, or partial antagonist.

As used herein, the term “antagonist” includes both full antagonists andpartial antagonists, as well as inverse agonists.

The term “compounds of the present invention” (unless specificallyidentified otherwise) refer to compounds of Formula (I) and Formula(II), prodrugs thereof, pharmaceutically acceptable salts of thecompounds, and/or prodrugs, and hydrates or solvates of the compounds,salts, and/or prodrugs, as well as, all stereoisomers (includingdiastereoisomers and enantiomers), tautomers and isotopically labeledcompounds.

DETAILED DESCRIPTION

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York(1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplements (also available viathe Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For a more detailed description of theindividual reaction steps, see the Examples section below. Those skilledin the art will appreciate that other synthetic routes may be used tosynthesize the inventive compounds. Although specific starting materialsand reagents are depicted in the schemes and discussed below, otherstarting materials and reagents can be easily substituted to provide avariety of derivatives and/or reaction conditions. In addition, many ofthe compounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will vary depending onthe nature of the remote functionality and the conditions of thepreparation methods. Suitable amino-protecting groups (NH-Pg) includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz)and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protectionis readily determined by one skilled in the art. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

Scheme I outlines the general procedures one could use to providecompounds of the present invention where A is C(R²) and R² and R³ arehydrogen, alkyl or halo substituted alkyl.

The pyrazole carboxylic acid (1a) may be prepared using the methodsdescribed in U.S. Pat. No. 5,624,941, incorporated herein by reference.Intermediate (1b) may be prepared by condensing the pyrazole carboxylicacid (a) with a protected α-aminoacetal or protected α-aminoketal (e.g.,N-benzylaminoacetaldehyde dimethyl acetal orN-benzyl-N-(2,2-diethoxyethyl)amine) using conditions well known tothose skilled in the art. For example intermediate (1b) may be formed bycoupling (1a) and the amine in an aprotic solvent (e.g., methylenechloride) at about room temperature using1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base(e.g., diisopropylethylamine). Cyclization to the pyridinone (1c) may beaccomplished using procedures described by Dumas, D. J., in J. Org.Chem., 53, 4650-1853 (1988) or by Brimble, M. A., et al., Aust. J.Chem., 41, 1583-1590 (1988). For example, pyridinone (1c) may be formedby treating (1b) with toluenesulfonic acid in refluxing toluene.Introduction of a leaving group (L) and aromatization of the pyridinone(1c) to form the aromatic intermediate (1d) may be accomplished usingconventional procedures well-known to those skilled in the art. Forexample, debenzylation/halogenation may be accomplished using phosphorusoxychloride under refluxing conditions. Alternatively, the protectinggroup could be cleaved as a first step, followed by halogenation (e.g.,POCl₃ or SOCl₂ in the presence or absence of a base like triethylamineor pyridine at reflux) or mesylation (e.g., methansulfonic anhydride andtertiary amine base).

When R⁴ is an amine functionality (e.g., R⁴=an amino group of Formula(IA) or an amino group substituted with one or more substituentsdescribed above), the amine may be introduced via a coupling reactionbetween intermediate (1d) and the corresponding amino compound (R⁴—H) togive a compound of the present invention where R⁴ is an amino group. Forexample, intermediate (1d) is generally stirred with the desired amine(R⁴—H). The amine may act as the solvent (e.g., butylamine, morpholine,pyrrolidine) or a solvent (e.g., methylene chloride,N,N-dimethylformamide, ethanol) may be added to assist in solubilizationof the reactants and/or provide a media having the appropriate refluxingtemperature to complete the substitution. The reaction may be heated toaccelerate the process. Suitable reaction temperatures range from about−40° C. to 100° C., and are preferably conducted at around 60° C. Inaddition, a suitable base (e.g., triethylamine, diisopropylethylamine)may be employed to quench the acid produced in the process. Suitableamino compounds can be either purchased commercially or easily preparedusing standard procedures well-known to those skilled in the art.Preferred amino compounds (R⁴—H) include4-alkylaminopiperidine-4-carboxamides (Scheme III) and3-alkylaminoazetidine-3-carboxamides that are described below. For adetailed description of representative compounds prepared using theprocedures generally described in Scheme I above where in R⁴ is an aminefunctionality, see Example 1A-1 in the Examples section below.

Scheme II below outlines the general procedures that may be used toproduce compounds of the present invention where A is N.

Lithium salt (2b) can be prepared by treatment of methyl ketone (2a)with lithium hexamethyldisilazide at a temperature of about −78° C. inan aprotic solvent such as THF, followed by condensation with diethyloxalate, as described in WO 00/46209. The isolated lithium salt (2b) isthen dissolved in an acid such as acetic acid and nitrosated by dropwiseaddition of aqueous sodium nitrite at a temperature of about 0-10° C.(Tetrahedron, 3, 209 (1958); Bull. Chem. Soc. Jpn. 52, 208 (1979)). Asubstituted hydrazine may then be added directly to the reaction mixtureto afford intermediate (2c). Cyclization of (c) is accomplished byheating intermediate (2c) and a catalytic amount of an acid such asconcentrated sulfuric acid in a solvent such isopropanol at atemperature of about 60° C. to provide nitrosopyrazole (d). The nitrosogroup of intermediate (2d) can be reduced by treatment of (2d) withsodium dithionite in a mixture of solvents such as ethyl acetate andwater, affording aminopyrazole (2e), which is reacted with anappropriate amidine (such as formamidine when R³═H) in an aproticsolvent such as 2-ethoxyethanol at an elevated temperature, such asreflux (202° C. for 2-ethoxyethanol) to provide pyrazolopyrimidine (2f).A leaving group (L) is then introduced in preparation for theintroduction of the R⁴ group. For example, chloropyrazolopyrimidineintermediate (g, where L is Cl) may be prepared by treatment of asuspension of (2f) in an aprotic solvent such as 1,2-dichloroethane withphosphorous oxychloride and heating the resultant suspension to reflux(83° C. for 1,2-dichloroethane). Compounds of formula I or II (A=N) arethen obtained by displacement of the leaving group (e.g., Cl) of (2g)with a nucleophile such as an amine in a solvent such as ethanol at atemperature of about 20-60° C. (see above). For a detailed descriptionof representative compounds prepared using the procedures generallydescribed in Scheme II above wherein R⁴ is an amine functionality, seeExamples 2A-1 and 3A-1 in the Examples section below.

Numerous amine compounds of Formula (IA) are available from commercialsources or prepared by known methods readily available to those skilledin the art. Representative preparations of amine compounds of Formula(IA) are illustrated in the Examples below. The4-aminopiperidine-4-carboxamide groups of Formula (IA) and4-amino-4-cyano piperidine groups of Formula (IA) and their benzylprotected precursors may be prepared using the procedures described byP. A. J. Janssen in U.S. Pat. No. 3,161,644, C. van de Westeringh et al.in J. Med. Chem., 7, 619-623 (1964), and K. A. Metwally et al. in J.Med. Chem., 41, 5084-5093 (1998) where the above 4-amino groups areunsubstituted, monosubstituted, disubstituted, or part of a heterocyclicring. Related bicyclic derivatives are described by K. Frohlich et al.in Tetrahedron, 54, 13115-13128 (1998) and references contained therein.Spiro-substituted piperidines of formula (IA) are described by P. A. J.Janssen in U.S. Pat. No. 3,155,670, K. A. Metwally et al. in J. Med.Chem., 41, 5084-5093 (1998), T. Toda et al. in Bull. Chem. Soc. Japan,44, 3445-3450 (1971), and W. Brandau and S. Samnick in WO 9522544. Thepreparation of 3-aminoazetidine-3-carboxamide is described by A. P.Kozikowski and A. H. Fauq in Synlett, 783-784 (1991). The preparation ofpreferred 4-alkylaminopiperidine-4-carboxamide groups of Formula (IA)are depicted in Scheme III below. The corresponding3-alkylaminoazetidine-3-carboxamides and3-alkylaminopyrrolidine-3-carboxamides may be prepared in an analogousfashion. Spiro-substituted derivatives are available by proceduresanalogous to those contained in the above references. A detaileddescription of some representative spiro-substituted amines may be foundin the “Preparation of Key Intermediates” section of the Examples below(see, e.g., I-2A-69d and I-3A-50d).

The amino group of 4-piperidinone is first protected to provideintermediate (3a). A useful protection group is benzyl. 4-Piperidinoneand derivatives thereof may be purchased commercially from a variety ofsources (e.g., Interchem Corporation, Paramus, N.J. and Sigma-AldrichCo., St. Louis, Mo.). Piperidinone (3a) may then be reacted with thedesired alkylamine and potassium cyamide in an aqueous HCl/ethanolsolvent mixture at about 0° C. to about 30° C. The cyano group isconverted to the corresponding amide with acid and water, or withalkaline hydrogen peroxide in the presence of DMSO (see Y. Sawaki and Y.Ogata in Bull. Chem. Soc. Jpn. 54, 793-799 (1981)). The protecting groupis then removed using conventional methods for the particular protectinggroup employed. For example, a benzyl protecting group may be removed byhydrogenation in the presence of Pd/C. A detailed description of somerepresentative amines having Formula (3c) above may be found in the“Preparation of Key Intermediates” section of the Examples below (see,e.g., I-1A-1f, I-2A-90a, and I-1A-6c).

Compounds of the present invention where R⁴ is an alkoxy group (i.e.,R⁴=a group of Formula (IB) or (1C), may be prepared by treatingintermediate (1d) or (mg) with the desired alcohol in the presence of abase (e.g., potassium t-butoxide, NaH, 1,4-diazabicyclo[2.2.2]octane,diisopropylethylamine, NaHCO₃). The alcohol may act as solvent, or anaprotic solvent may be added to assist in solubilization of thereactants and/or provide a media having the appropriate refluxingtemperature to complete the substitution (e.g., THF, methylene chloride,DMF). Suitable alcohols can be either purchased commercially or easilyprepared using standard procedures well known to those skilled in theart. For a detailed description of representative compounds preparedusing this procedure, see Examples 7A-1, 8A-1, 9A-1 and 12A-1 in theExamples section below.

An alternative route to compounds where R⁴ is an alkoxy group involvesO-alkylation of the pyrazolopyrimidinol (2f) or pyrazolopyrimidinol. Thelatter intermediate can be prepared by deprotecting (1c) using standardprocedures. Alternatively, the pyrazolopyrimidinol can be prepared byhydrolyzing intermediate (1d), such as by heating with aqueous acid(e.g., HCl) in an appropriate solvent (e.g., THF). For a detaileddescription of representative compounds prepared using this procedure,see Example 10A-1 in the Examples section below.

For compounds of Formula (I) and (II) where R⁴ is an aminoalkyl,alkylaminoalkyl, or dialkylaminoalkyl group, the leaving group (e.g.,L=Cl) in intermediate (1d) or (2g) may first be displaced with a cyanogroup (e.g., treating with tetrabutylammonium cyamide in the presence of1,4-diazabicyclo[2.2.2]octane (DABCO) in an aprotic solvent (e.g.,acetonitrile) at room temperature). See, e.g., Hocek, et al. Collect.Czech. Chem. Commun. 60, 1386 (1995). The cyano group may then bereduced to the alkyl amine using standard reduction methods well-knownto those skilled in the art (e.g., treating with DIBAL or hydrogen inthe presence of Pd/C). The amino group can then be alkylated usingstandard reductive alkylation procedures. Generally, a Schiff base isformed by reacting the amine with the desired ketone or aldehyde in apolar solvent at a temperature from about 10° C. to about 140° C. forabout 2 to about 24 hours in the presence of 3 Å molecular sieves.Typically, an equivalent or a slight excess of the amino compound isadded to the ketone or aldehyde. Suitable polar solvents includemethylene chloride, 1,2-dichloroethane, dimethyl sulfoxide,dimethylformamide, alcohols (e.g., methanol or ethanol), or mixturesthereof. A preferred solvent is methanol. In the same reaction vessel,the imine may then be reduced to the secondary amine in the presence ofa reducing agent at a temperature from about 0° C. to about 10° C. andthen warmed to a temperature from about 20° C. to about 40° C. for about30 minutes to about 2 hours. Suitable reducing agents includepyridine-borane complex and metal borohydrides, such as sodiumborohydride, sodium triacetoxy borohydride and sodium cyanoborohydride.Suitable aldehydes or ketones include paraformaldehyde, acetaldehyde,acetone, benzaldehyde, and the like.

Alternatively, the amino alkyl group may be introduced using the methodsdescribed by Hocek, et al. in Tetrahedron, 53(6), 2291-2302 (1997).Intermediate (1d), where L=Cl, Br or OTf, or intermediate (2g) may beconverted to the acetyl-derivative compound by reacting intermediate(1d) or (2g) with 1-ethoxyvinyl)tri-n-butyltin under Pd(PPh₃)₄ catalysisfollowed by hydrolysis using a mixture of acetone and aqueous HCl (orDMF/aq. HCl mixture) at reflux temperatures. The acetyl group may thenbe converted to an amine or substituted amine by reductive amination, aprocess well-known to those skilled in the art. An exemplary procedureemploys the desired amine salt (e.g., ammonium chloride, methylammoniumchloride, allylammonium chloride, cyclopropylammonium chloride,cyclohexylammonium chloride, dimethylammonium chloride, benzylammoniumchloride, etc.) and a reducing agent (e.g., NaBH₄, NaBH₃CN, ortriacetoxyborohydride) in polar solvent at room temperature. SeeAbdel-Magid, et al., J. Org. Chem., 61, 3849-3862 (1996) for a widevariety of aldehydes, ketones and amines that may be used in either thereductive alkylation or the reductive amination.

Compounds of Formula (I) above where R⁴ contains a primary or secondaryamine can be alkylated, sulfonated and/or acylated to provide additionalderivatives (e.g., alkylamines, dialkylamines, sulfonamides, amides,carbamates, ureas, etc.) using standard procedures well known to thoseskilled in the art. In some cases the amine is protected, and must beunmasked before further functionalization. For a more detaileddescription of representative compounds prepared using these procedures,see Examples 4A-1, 5A-1 and 6A-1 in the Examples section below.

Alternatively, compounds of Formula (I) or (II) where R⁴ is a hydroxy oralkoxy substituted alkyl group may be produced by replacing the chlorinegroup of intermediate (1d), L=Cl, or (2g) with the desired electrophileusing procedures described by Sugimoto, et al., in Tetrahedron Letters,40, 2139-2140 (1999). The intermediate (1d), L=Cl, or (2a) may bereacted with lithium n-butanetellurolate (tellurium reacted withn-butyllithium) in an aprotic solvent (e.g., THF) at −78° C. followed bythe addition of the desired electrophile (e.g., acetaldehyde,benzaldehyde, acetone, methylethyl ketone, etc.) and then warmed to roomtemperature to form the desired hydroxyalkyl derivative. Alternately,the hydroxy derivative may be formed using the procedures described byLeonard, et al., in J. Org. Chem., 44(25), 4612-4616 (1979).Intermediate (1d), L=Cl, or (2g) is treated with n-butyl lithium to formthe carbanion at −78° C., followed by reaction with the desiredelectrophile (e.g., ketone or aldehyde) to form the hydroxyalkylderivative.

In yet another approach, an aroyl derivative of formula (I) or (II),where R⁴=aroyl, can be prepared by the procedures described byMiyashita, et al., in Chem. Pharm. Bull, 46(30), 390-399 (1998). Thearoyl group can then be reduced to the corresponding secondary alcoholby treating with a reducing agent such as lithium aluminum hydride. Thetertiary alcohol can be obtained upon treatment with an alkyl metalreagent, such as an alkyl Grignard reagent, in a suitable solvent (e.g.,tetrahydrofuran, diethyl ether). Finally, an amine could be introducedby reductive amination (see above).

In the above examples, the resultant hydroxyalkyl group can then bealkylated or acylated to form the desired alkoxy or acylate (e.g.,(alkyl)-C(O)—O—, (aryl)-C(O)—O—, (heteroaryl)-C(O)—O—, etc.) usingstandard procedures well-known to those skilled in the art.Alternatively, the hydroxy group may be condensed with other moieties toprovide a variety of substituents (e.g., sulfamyl, sulfonyl, etc.). Theaminoalkyl group could be modified in a similar fashion to give amides,sulfonamides, etc.

An alternate route for the synthesis of intermediate (2e) is shown inScheme IV below.

The starting pyrazolo ester (R=alkyl group) may be prepared byprocedures described in U.S. Pat. No. 5,624,941 and is incorporatedherein by reference. The bromo intermediate (4b) may be prepared from(a) using conventional bromination procedures well-known to thoseskilled in the art. For example, the pyrazolo ester may be treated withbromine in a protic solvent (e.g., acetic acid) at a temperature fromabout 10° C. to about −10° C. Amine deriviative (4c), which isequivalent to (2e) when R=Et, may then be prepared bypalladium-catalyzed methods described by X. Huang and S. L. Buchwald inOrg. Lett., 3, 3417-3419 (2001), and with references contained therein.

Conventional methods and/or techniques of separation and purificationknown to one of ordinary skill in the art can be used to isolate thecompounds of the present invention, as well as the various intermediatesrelated thereto. Such techniques will be well known to one of ordinaryskill in the art and may include, for example, all types ofchromatography (high pressure liquid chromatography (HPLC), columnchromatography using common adsorbents such as silica gel, andthin-layer chromatography), recrystallization, and differential (i.e.,liquid-liquid) extraction techniques.

The compounds of the present invention may be isolated and used per seor in the form of its pharmaceutically acceptable salt, solvate and/orhydrate. The term “salts” refers to inorganic and organic salts of acompound of the present invention. These salts can be prepared in situduring the final isolation and purification of a compound, or byseparately reacting the compound, N-oxide, or prodrug with a suitableorganic or inorganic acid or base and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride,hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate,oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate,malate, borate, benzoate, lactate, phosphate, hexafluorophosphate,benzene sulfonate, tosylate, formate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts, and the like. These mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. See, e.g., Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

The term “prodrug” means a compound that is transformed in vivo to yielda compound of Formula (I) or a pharmaceutically acceptable salt, hydrateor solvate of the compound. The transformation may occur by variousmechanisms, such as through hydrolysis in blood. A discussion of the useof prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as NovelDelivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a compound of the present invention contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and x-aminoacyl, orα-aminoacyl-α-aminoacyl, where each x-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from the removalof a hydroxyl group of the hemiacetal form of a carbohydrate).

If a compound of the present invention incorporates an amine functionalgroup, a prodrug can be formed by the replacement of a hydrogen atom inthe amine group with a group such as R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY′ wherein Y′ is H,(C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ wherein Y₀ is (C₁-C₄) alkyl and Y₁ is(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃ wherein Y₂ is H or methyl and Y₃is mono-N- or di-N,N—(C₁-C₆)alkylamino, morpholino, piperidin-1-yl orpyrrolidin-1-yl.

The compounds of the present invention may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of the presentinvention as well as mixtures thereof, including racemic mixtures, formpart of the present invention. In addition, the present inventionembraces all geometric and positional isomers. For example, if acompound of the present invention incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Both the single positional isomersand mixture of positional isomers resulting from the N-oxidation of thepyrimidine and pyrazine rings are also within the scope of the presentinvention.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

It is also possible that the compounds of the present invention mayexist in different tautomeric forms, and all such forms are embracedwithin the scope of the invention. The term “tautomer” or “tautomericform” refers to structural isomers of different energies which areinterconvertible via a low energy barrier. For example, proton tautomers(also known as prototropic tautomers) include interconversions viamigration of a proton, such as keto-enol and imine-enamineisomerizations. Valence tautomers include interconversions byreorganization of some of the bonding electrons.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S,¹⁸F, ¹²³I, ¹²⁵I and ³⁶Cl, respectively.

Certain isotopically-labeled compounds of the present invention (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent invention can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

Compounds of the present invention are useful for treating diseases,conditions and/or disorders modulated by cannabinoid receptorantagonists; therefore, another embodiment of the present invention is apharmaceutical composition comprising a therapeutically effective amountof a compound of the present invention and a pharmaceutically acceptableexcipient, diluent or carrier.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water, and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients described above. The compound of the presentinvention is typically formulated into pharmaceutical dosage forms toprovide an easily controllable dosage of the drug and to give thepatient an elegant and easily handleable product.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present invention further provides a method of treating diseases,conditions and/or disorders modulated by cannabinoid receptorantagonists in an animal that includes administering to an animal inneed of such treatment a therapeutically effective amount of a compoundof the present invention or a pharmaceutical composition comprising aneffective amount of a compound of the present invention and apharmaceutically acceptable excipient, diluent, or carrier. The methodis particularly useful for treating diseases, conditions and/ordisorders modulated by cannabinoid receptor (in particular, CB1receptor) antagonists.

Preliminary investigations have indicated that the following diseases,conditions, and/or disorders are modulated by cannabinoid receptorantagonists: eating disorders (e.g., binge eating disorder, anorexia,and bulimia), weight loss or control (e.g., reduction in calorie or foodintake, and/or appetite suppression), obesity, depression, atypicaldepression, bipolar disorders, psychoses, schizophrenia, behavioraladdictions, suppression of reward-related behaviors (e.g., conditionedplace avoidance, such as suppression of cocaine- and morphine-inducedconditioned place preference), substance abuse, addictive disorders,impulsivity, alcoholism (e.g., alcohol abuse, addiction and/ordependence including treatment for abstinence, craving reduction andrelapse prevention of alcohol intake), tobacco abuse (e.g., smokingaddiction, cessation and/or dependence including treatment for cravingreduction and relapse prevention of tobacco smoking), dementia(including memory loss, Alzheimer's disease, dementia of aging, vasculardementia, mild cognitive impairment, age-related cognitive decline, andmild neurocognitive disorder), sexual dysfunction in males (e.g.,erectile difficulty), seizure disorders, epilepsy, inflammation,gastrointestinal disorders (e.g., dysfunction of gastrointestinalmotility or intestinal propulsion), attention deficit disorder (ADDincluding attention deficit hyperactivity disorder (ADHD)), Parkinson'sdisease, and type II diabetes. Accordingly, the compounds of the presentinvention described herein are useful in treating diseases, conditions,or disorders that are modulated by cannabinoid receptor antagonists.Consequently, the compounds of the present invention (including thecompositions and processes used therein) may be used in the manufactureof a medicament for the therapeutic applications described herein.

Other diseases, conditions and/or disorders for which cannabinoidreceptor antagonists may be effective include: premenstrual syndrome orlate luteal phase syndrome, migraines, panic disorder, anxiety,post-traumatic syndrome, social phobia, cognitive impairment innon-demented individuals, non-amnestic mild cognitive impairment, postoperative cognitive decline, disorders associated with impulsivebehaviours (such as, disruptive behaviour disorders (e.g.,anxiety/depression, executive function improvement, tic disorders,conduct disorder and/or oppositional defiant disorder), adultpersonality disorders (e.g., borderline personality disorder andantisocial personality disorder), diseases associated with impulsivebehaviours (e.g., substance abuse, paraphilias and self-mutilation), andimpulse control disorders (e.g., intermittene explosive disorder,kleptomania, pyromania, pathological gambling, and trichotillomania)),obsessive compulsive disorder, chronic fatigue syndrome, sexualdysfunction in males (e.g., premature ejaculation), sexual dysfunctionin females, disorders of sleep (e.g., sleep apnea), autism, mutism,neurodengenerative movement disorders, spinal cord injury, damage of thecentral nervous system (e.g., trauma), stroke, neurodegenerativediseases or toxic or infective CNS diseases (e.g., encephalitis ormeningitis), cardiovascular disorders (e.g., thrombosis), and diabetes.

The compounds of the present invention can be administered to a patientat dosage levels in the range of from about 0.7 mg to about 7,000 mg perday. For a normal adult human having a body weight of about 70 kg, adosage in the range of from about 0.01 mg to about 100 mg per kilogrambody weight is typically sufficient. However, some variability in thegeneral dosage range may be required depending upon the age and weightof the subject being treated, the intended route of administration, theparticular compound being administered and the like. The determinationof dosage ranges and optimal dosages for a particular patient is wellwithin the ability of one of ordinary skill in the art having thebenefit of the instant disclosure. It is also noted that the compoundsof the present invention can be used in sustained release, controlledrelease, and delayed release formulations, which forms are also wellknown to one of ordinary skill in the art.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents for the treatment of the diseases,conditions and/or disorders described herein. Therefore, methods oftreatment that include administering compounds of the present inventionin combination with other pharmaceutical agents are also provided.Suitable pharmaceutical agents that may be used in combination with thecompounds of the present invention include anti-obesity agents such asapolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, 11β-hydroxy steroid dehydrogenase-1 (11β-HSDtype 1) inhibitors, peptide YY₃₋₃₆ or analogs thereof, MCR-4 agonists,cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (suchas sibutramine), sympathomimetic agents, 3 adrenergic receptor agonists,dopamine agonists (such as bromocriptine), melanocyte-stimulatinghormone receptor analogs, 5HT2c agonists, melanin concentrating hormoneantagonists, leptin (the OB protein), leptin analogs, leptin receptoragonists, galanin antagonists, lipase inhibitors (such astetrahydrolipstatin, i.e. orlistat), anorectic agents (such as abombesin agonist), Neuropeptide-Y receptor antagonists (e.g., NPY Y5receptor antagonists, such as the spiro compounds described in U.S. Pat.Nos. 6,566,367; 6,649,624; 6,638,942; 6,605,720; 6,495,559; 6,462,053;6,388,077; 6,335,345; and 6,326,375; US Publication Nos. 2002/0151456and 2003/036652; and PCT Publication Nos. WO 03/010175. WO 03/082190 andWO 02/048152), thyromimetic agents, dehydroepiandrosterone or an analogthereof, glucocorticoid receptor agonists or antagonists, orexinreceptor antagonists, glucagon-like peptide-1 receptor agonists, ciliaryneurotrophic factors (such as Axokine™ available from RegeneronPharmaceuticals, Inc., Tarrytown, N.Y. and Procter & Gamble Company,Cincinnati, Ohio), human agouti-related proteins (AGRP), ghrelinreceptor antagonists, histamine 3 receptor antagonists or inverseagonists, neuromedin U receptor agonists and the like. Otheranti-obesity agents, including the preferred agents set forthhereinbelow, are well known, or will be readily apparent in light of theinstant disclosure, to one of ordinary skill in the art.

Especially preferred are anti-obesity agents selected from the groupconsisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin,pseudoephedrine; peptide YY₃₋₃₆ or an analog thereof; and2-oxo-N-(5-phenylpyrazinyl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide. Preferably, compounds of the presentinvention and combination therapies are administered in conjunction withexercise and a sensible diet.

Representative anti-obesity agents for use in the combinations,pharmaceutical compositions, and methods of the invention can beprepared using methods known to one of ordinary skill in the art, forexample, sibutramine can be prepared as described in U.S. Pat. No.4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos.3,752,814 and 3,752,888; orlistat can be prepared as described in U.S.Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874; PYY₃₋₃₆(including analogs) can be prepared as described in US Publication No.2002/0141985 and WO 03/027637; and the NPY Y5 receptor antagonist2-oxo-N-(5-phenylpyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide can be prepared as described in USPublication No. 2002/0151456. Other useful NPY Y5 receptor antagonistsinclude those described in PCT Publication No. 03/082190, such as3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide;3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)-spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide;N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),[4′-piperidine]-1′-carboxamide;trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide;trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide;trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide; and pharmaceutically acceptable saltsand esters thereof. All of the above recited U.S. patents andpublications are incorporated herein by reference.

Other suitable pharmaceutical agents that may be administered incombination with the compounds of the present invention include agentsdesigned to treat tobacco abuse (e.g., nicotine receptor partialagonists, bupropion hypochloride (also known under the tradename Zyban™)and nicotine replacement therapies), agents to treat erectiledysfunction (e.g., dopaminergic agents, such as apomorphine), ADD/ADHDagents (e.g., Ritalin™, Strattera™, Concerta™ and Adderall™), and agentsto treat alcoholism, such as opioid antagonists (e.g., naltrexone (alsoknown under the tradename ReVia™) and nalmefene), disulfiram (also knownunder the tradename Antabuse™), and acamprosate (also known under thetradename Campral™)). In addition, agents for reducing alcoholwithdrawal symptoms may also be co-administered, such asbenzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin,and gabapentin (Neurontin™). Treatment for alcoholism is preferablyadministered in combination with behavioral therapy including suchcomponents as motivational enhancement therapy, cognitive behavioraltherapy, and referral to self-help groups, including Alcohol Anonymous(AA).

Other pharmaceutical agents that may be useful include antihypertensiveagents; anti-inflammatory agents (e.g., COX-2 inhibitors);antidepressants (e.g., fluoxetine hydrochloride (Prozac™)); cognitiveimprovement agents (e.g., donepezil hydrochloride (Aircept™) and otheracetylcholinesterase inhibitors); neuroprotective agents (e.g.,memantine); antipsychotic medications (e.g., ziprasidone (Geodon™),risperidone (Risperdal™), and olanzapine (Zyprexa™)); insulin andinsulin analogs (e.g., LysPro insulin); GLP-1 (7-37) (insulinotropin)and GLP-1 (7-36)-NH₂; sulfonylureas and analogs thereof: chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide®,glimepiride, repaglinide, meglitinide; biguanides; metformin,phenformin, buformin; α2-antagonists and imidazolines; midaglizole,isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulinsecretagogues: linogliride, A-4166; glitazones: ciglitazone, Actos®(pioglitazone), englitazone, troglitazone, darglitazone, Avandia®(BRL49653); fatty acid oxidation inhibitors: clomoxir, etomoxir;α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose,MDL-25,637, camiglibose, MDL-73,945; β-agonists: BRL 35135, BRL 37344,RO 16-8714, ICI D7114, CL 316,243; phosphodiesterase inhibitors:L-386,398; lipid-lowering agents: benfluorex: fenfluramine; vanadate andvanadium complexes (e.g., Naglivan®) and peroxovanadium complexes;amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors;somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox,WAG 994, pramlintide (Symlin™), AC 2993, nateglinide, aldose reductaseinhibitors (e.g., zopolrestat), glycogen phosphorylase inhibitors,sorbitol dehydrogenase inhibitors, sodium-hydrogen exchanger type 1(NHE-1) inhibitors and/or cholesterol biosynthesis inhibitors orcholesterol absorption inhibitors, especially a HMG-CoA reductaseinhibitor (e.g., atorvastatin or the hemicalcium salt thereof), or aHMG-CoA synthase inhibitor, or a HMG-CoA reductase or synthase geneexpression inhibitor, a CETP inhibitor, a bile acid sequesterant, afibrate, an ACAT inhibitor, a squalene synthetase inhibitor, ananti-oxidant or niacin. The compounds of the present invention may alsobe administered in combination with a naturally occurring compound thatacts to lower plasma cholesterol levels. Such naturally occurringcompounds are commonly called nutraceuticals and include, for example,garlic extract, Hoodia plant extracts, and niacin.

The dosage of the additional pharmaceutical agent is generally dependentupon a number of factors including the health of the subject beingtreated, the extent of treatment desired, the nature and kind ofconcurrent therapy, if any, and the frequency of treatment and thenature of the effect desired. In general, the dosage range of theadditional pharmaceutical agent is in the range of from about 0.001 mgto about 100 mg per kilogram body weight of the individual per day,preferably from about 0.1 mg to about 10 mg per kilogram body weight ofthe individual per day. However, some variability in the general dosagerange may also be required depending upon the age and weight of thesubject being treated, the intended route of administration, theparticular anti-obesity agent being administered and the like. Thedetermination of dosage ranges and optimal dosages for a particularpatient is also well within the ability of one of ordinary skill in theart having the benefit of the instant disclosure.

According to the methods of the invention, a compound of the presentinvention or a combination of a compound of the present invention and atleast one additional pharmaceutical agent is administered to a subjectin need of such treatment, preferably in the form of a pharmaceuticalcomposition. In the combination aspect of the invention, the compound ofthe present invention and at least one other pharmaceutical agent (e.g.,anti-obesity agent, nicotine receptor partial agonist, dopaminergicagent, or opioid antagonist) may be administered either separately or inthe pharmaceutical composition comprising both. It is generallypreferred that such administration be oral. However, if the subjectbeing treated is unable to swallow, or oral administration is otherwiseimpaired or undesirable, parenteral or transdermal administration may beappropriate.

According to the methods of the invention, when a combination of acompound of the present invention and at least one other pharmaceuticalagent are administered together, such administration can be sequentialin time or simultaneous with the simultaneous method being generallypreferred. For sequential administration, a compound of the presentinvention and the additional pharmaceutical agent can be administered inany order. It is generally preferred that such administration be oral.It is especially preferred that such administration be oral andsimultaneous. When a compound of the present invention and theadditional pharmaceutical agent are administered sequentially, theadministration of each can be by the same or by different methods.

According to the methods of the invention, a compound of the presentinvention or a combination of a compound of the present invention and atleast one additional pharmaceutical agent (referred to herein as a“combination”) is preferably administered in the form of apharmaceutical composition. Accordingly, a compound of the presentinvention or a combination can be administered to a patient separatelyor together in any conventional oral, rectal, transdermal, parenteral,(for example, intravenous, intramuscular, or subcutaneous)intracisternal, intravaginal, intraperitoneal, intravesical, local (forexample, powder, ointment or drop), or buccal, or nasal, dosage form.

Compositions suitable for parenteral injection generally includepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Suitable aqueous and nonaqueous carriers or diluents (including solventsand vehicles) include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain excipients such as preserving,wetting, emulsifying, and dispersing agents. Prevention of microorganismcontamination of the compositions can be accomplished with variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride, and the like. Prolonged absorption of injectablepharmaceutical compositions can be brought about by the use of agentscapable of delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, a compound of thepresent invention or a combination is admixed with at least one inertexcipient, diluent or carrier. Suitable excipients, diluents or carriersinclude materials such as sodium citrate or dicalcium phosphate or (a)fillers or extenders (e.g., starches, lactose, sucrose, mannitol,silicic acid and the like); (b) binders (e.g., carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like);(c) humectants (e.g., glycerol and the like); (d) disintegrating agents(e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain complex silicates, sodium carbonate and the like); (e)solution retarders (e.g., paraffin and the like); (f) absorptionaccelerators (e.g., quaternary ammonium compounds and the like); (g)wetting agents (e.g., cetyl alcohol, glycerol monostearate and thelike); (h) adsorbents (e.g., kaolin, bentonite and the like); and/or (i)lubricants (e.g., talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate and the like). In the caseof capsules and tablets, the dosage forms may also comprise bufferingagents. Solid compositions of a similar type may also be used as fillersin soft or hard filled gelatin capsules using such excipients as lactoseor milk sugar, as well as high molecular weight polyethylene glycols,and the like.

Solid dosage forms such as tablets, dragees, capsules, and granules canbe prepared with coatings and shells, such as enteric coatings andothers well known in the art. They may also contain opacifying agents,and can also be of such composition that they release the compound ofthe present invention and/or the additional pharmaceutical agent in adelayed manner. Examples of embedding compositions that can be used arepolymeric substances and waxes. The drug can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the compound of the present invention or the combination,the liquid dosage form may contain inert diluents commonly used in theart, such as water or other solvents, solubilizing agents andemulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseedoil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seedoil and the like), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, or mixtures of thesesubstances, and the like.

Besides such inert diluents, the composition can also includeexcipients, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the compound of the present invention or thecombination, may further comprise carriers such as suspending agents,e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol andsorbitan esters, microcrystalline cellulose, aluminum metahydroxide,bentonite, agar-agar, and tragacanth, or mixtures of these substances,and the like.

Compositions for rectal or vaginal administration preferably comprisesuppositories, which can be prepared by mixing a compound of the presentinvention or a combination with suitable non-irritating excipients orcarriers, such as cocoa butter, polyethylene glycol or a suppository waxwhich are solid at ordinary room temperature but liquid at bodytemperature and therefore melt in the rectum or vaginal cavity therebyreleasing the active component(s).

Dosage forms for topical administration of the compounds of the presentinvention and combinations of the compounds of the present inventionwith anti-obesity agents may comprise ointments, powders, sprays andinhalants. The drugs are admixed under sterile conditions with apharmaceutically acceptable excipient, diluent or carrier, and anypreservatives, buffers, or propellants that may be required. Ophthalmicformulations, eye ointments, powders, and solutions are also intended tobe included within the scope of the present invention.

The following paragraphs describe exemplary formulations, dosages, etc.useful for non-human animals. The administration of the compounds of thepresent invention and combinations of the compounds of the presentinvention with anti-obesity agents can be effected orally or non-orally(e.g., by injection).

An amount of a compound of the present invention or combination of acompound of the present invention with an anti-obesity agent isadministered such that an effective dose is received. Generally, a dailydose that is administered orally to an animal is between about 0.01 andabout 1,000 mg/kg of body weight, preferably between about 0.01 andabout 300 mg/kg of body weight.

Conveniently, a compound of the present invention (or combination) canbe carried in the drinking water so that a therapeutic dosage of thecompound is ingested with the daily water supply. The compound can bedirectly metered into drinking water, preferably in the form of aliquid, water-soluble concentrate (such as an aqueous solution of awater-soluble salt).

Conveniently, a compound of the present invention (or combination) canalso be added directly to the feed, as such, or in the form of an animalfeed supplement, also referred to as a premix or concentrate. A premixor concentrate of the compound in an excipient, diluent or carrier ismore commonly employed for the inclusion of the agent in the feed.Suitable carriers are liquid or solid, as desired, such as water,various meals such as alfalfa meal, soybean meal, cottonseed oil meal,linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal,and mineral mixes such as are commonly employed in poultry feeds. Aparticularly effective carrier is the respective animal feed itself;that is, a small portion of such feed. The carrier facilitates uniformdistribution of the compound in the finished feed with which the premixis blended. Preferably, the compound is thoroughly blended into thepremix and, subsequently, the feed. In this respect, the compound may bedispersed or dissolved in a suitable oily vehicle such as soybean oil,corn oil, cottonseed oil, and the like, or in a volatile organic solventand then blended with the carrier. It will be appreciated that theproportions of compound in the concentrate are capable of wide variationsince the amount of the compound in the finished feed may be adjusted byblending the appropriate proportion of premix with the feed to obtain adesired level of compound.

High potency concentrates may be blended by the feed manufacturer withproteinaceous carrier such as soybean oil meal and other meals, asdescribed above, to produce concentrated supplements, which are suitablefor direct feeding to animals. In such instances, the animals arepermitted to consume the usual diet. Alternatively, such concentratedsupplements may be added directly to the feed to produce a nutritionallybalanced, finished feed containing a therapeutically effective level ofa compound of the present invention. The mixtures are thoroughly blendedby standard procedures, such as in a twin shell blender, to ensurehomogeneity.

If the supplement is used as a top dressing for the feed, it likewisehelps to ensure uniformity of distribution of the compound across thetop of the dressed feed.

Drinking water and feed effective for increasing lean meat depositionand for improving lean meat to fat ratio are generally prepared bymixing a compound of the present invention with a sufficient amount ofanimal feed to provide from about 10⁻³ to about 500 ppm of the compoundin the feed or water.

The preferred medicated swine, cattle, sheep and goat feed generallycontain from about 1 to about 400 grams of a compound of the presentinvention (or combination) per ton of feed, the optimum amount for theseanimals usually being about 50 to about 300 grams per ton of feed.

The preferred poultry and domestic pet feeds usually contain about 1 toabout 400 grams and preferably about 10 to about 400 grams of a compoundof the present invention (or combination) per ton of feed.

For parenteral administration in animals, the compounds of the presentinvention (or combination) may be prepared in the form of a paste or apellet and administered as an implant, usually under the skin of thehead or ear of the animal in which increase in lean meat deposition andimprovement in lean meat to fat ratio is sought.

In general, parenteral administration involves injection of a sufficientamount of a compound of the present invention (or combination) toprovide the animal with about 0.01 to about 20 mg/kg/day of body weightof the drug. The preferred dosage for poultry, swine, cattle, sheep,goats and domestic pets is in the range of from about 0.05 to about 10mg/kg/day of body weight of drug.

Paste formulations can be prepared by dispersing the drug in apharmaceutically acceptable oil such as peanut oil, sesame oil, corn oilor the like.

Pellets containing an effective amount of a compound of the presentinvention, pharmaceutical composition, or combination can be prepared byadmixing a compound of the present invention or combination with adiluent such as carbowax, carnuba wax, and the like, and a lubricant,such as magnesium or calcium stearate, can be added to improve thepelleting process.

It is, of course, recognized that more than one pellet may beadministered to an animal to achieve the desired dose level which willprovide the increase in lean meat deposition and improvement in leanmeat to fat ratio desired. Moreover, implants may also be madeperiodically during the animal treatment period in order to maintain theproper drug level in the animal's body.

The present invention has several advantageous veterinary features. Forthe pet owner or veterinarian who wishes to increase leanness and/ortrim unwanted fat from pet animals, the instant invention provides themeans by which this may be accomplished. For poultry, beef and swinebreeders, utilization of the method of the present invention yieldsleaner animals that command higher sale prices from the meat industry.

Embodiments of the present invention are illustrated by the followingExamples. It is to be understood, however, that the embodiments of theinvention are not limited to the specific details of these Examples, asother variations thereof will be known, or apparent in light of theinstant disclosure, to one of ordinary skill in the art.

EXAMPLES

Unless specified otherwise, starting materials are generally availablefrom commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wis.),Lancaster Synthesis, Inc. (Windham, N.H.), Acros Organics (Fairlawn,N.J.), Maybridge Chemical Company, Ltd. (Cornwall, England), TygerScientific (Princeton, N.J.), and AstraZeneca Pharmaceuticals (London,England).

The acronyms listed below have the following corresponding meanings:

-   -   LiN(TMS)—2-lithium hexamethyldisilazide    -   PS-DIEA—polystyrene-bound diisopropylethylamine (available from        Argonaut Technologies, Foster City, Calif.)

General Experimental Procedures

NMR spectra were recorded on a Varian Unity™ 400 or 500 (available fromVarian Inc., Palo Alto, Calif.) at room temperature at 400 and 500 MHz¹H, respectively. Chemical shifts are expressed in parts per million (δ)relative to residual solvent as an internal reference. The peak shapesare denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; br s, broad singlet; v br s, very broad singlet; br m,broad multiplet; 2s, two singlets. In some cases only representative ¹HNMR peaks are given.

Mass spectra were recorded by direct flow analysis using positive andnegative atmospheric pressure chemical ionization (APcl) scan modes. AWaters APcl/MS model ZMD mass spectrometer equipped with Gilson 215liquid handling system was used to carry out the experiments

Mass spectrometry analysis was also obtained by RP-HPLC gradient methodfor chromatographic separation. Molecular weight identification wasrecorded by positive and negative electrospray ionization (ESI) scanmodes. A Waters/Micromass ESI/MS model ZMD or LCZ mass spectrometerequipped with Gilson 215 liquid handling system and HP 1100 DAD was usedto carry out the experiments.

Where the intensity of chlorine or bromine-containing ions aredescribed, the expected intensity ratio was observed (approximately 3:1for ³⁵Cl/³⁷Cl-containing ions and 1:1 for ⁷⁹Br/⁸¹Br-containing ions) andonly the lower mass ion is given. MS peaks are reported for allexamples.

Optical rotations were determined on a PerkinElmer™ 241 polarimeter(available from PerkinElmer Inc., Wellesley, Mass.) using the sodium Dline (λ=589 nm) at the indicated temperature and are reported as follows[α]_(D) ^(temp), concentration (c=g/100 ml), and solvent.

Column chromatography was performed with either Baker™ silica gel (40μm; J. T. Baker, Phillipsburg, N.J.) or Silica Gel 50 (EM Sciences™,Gibbstown, N.J.) in glass columns or in Biotage™ columns (ISC, Inc.,Shelton, Conn.) under low nitrogen pressure. Radial chromatography wasperformed using a Chromatotron™ (Harrison Research).

Preparation of Key Intermediates Preparation of Intermediate5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid(2,2-diethoxyethyl)-amide (I-1A-1a)

To a stirred solution of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid(prepared according to the methods described by Barth, et al. in U.S.Pat. No. 5,624,941); 740 mg, 2.01 mmol) andN-benzyl-N-(2,2-diethoxyethyl)amine (450 mg, 2.01 mmol) in methylenechloride (6.5 ml) at room temperature was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (464 mg,2.42 mmol) and then diisopropylethylamine (0.42 ml, 2.2 mmol), dropwise.After stirring for 23 hours, the reaction mixture was concentrated, invacuo, and then extracted from saturated aqueous sodium bicarbonate withethyl acetate. The combined organic layers were washed with brine, dried(MgSO₄), and concentrated, in vacuo. The crude material (1.05 g) waspurified on a Biotage™ Flash 40S column using 0-20% ethyl acetate inhexanes as eluant to afford I-1A-1a as a foam (534 mg, 46%): +ESI MS(M+1) 572.1; ¹H NMR (500 MHz, CD₂Cl₂) 1:1 mixture of rotamers, δ 7.51(br s, 0.5H), 7.47 (d, J=2.1 Hz, 0.5H), 7.38-7.34 (m, 2H), 7.38-7.23 (m,9H), 7.18-7.11 (m, 2H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 5.22 (s, 1H),4.91 (s, 1H), 4.83-4.79 (m, 1H), 3.56-3.07 (m, 6H), 1.20 (t, J=7.0 Hz,3H), 1.07 (t, J=7.0 Hz, 3H).

Preparation of Intermediate6-Benzyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2,6-dihydropyrazolo[3,4-c]pyridin-7-one(I-1A-1b)

A mixture of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid(2,2-diethoxyethyl)-amide (I-1A-1a; 528 mg, 0.92 mmol) andp-toluenesulfonic acid monohydrate (175 mg, 0.92 mmol) in toluene (5 ml)was heated to reflux in round bottom flask fitted with a Dean-Starkcondenser. After 1 hour, the reaction mixture was cooled to roomtemperature, and then extracted from saturated aqueous sodiumbicarbonate with ethyl acetate. The combined organic layers were washedwith brine, dried (MgSO₄), and concentrated in vacuo. The crude material(0.49 g) was purified on a Biotage™ Flash 40S column using 10-20-40%ethyl acetate in hexanes as eluant to afford I-1A-1b as a solid (69 mg,16%): +ESI MS (M+1) 480.1; ¹H NMR (500 MHz, CD₂Cl₂) δ 7.50 (d, J=1.5 Hz,1H), 7.48 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.3, 2.1 Hz, 1H), 7.38-7.27 (m,7H), 7.18 (d, J=8.7 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.42 (d, J=7.5 Hz,1H), 5.21 (s, 2H).

Preparation of Intermediate7-Chloro-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-1c)

A stirred suspension of6-benzyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2,6-dihydropyrazolo[3,4-c]pyridin-7-one(I-1A-1b; 153 mg, 0.32 mmol) in POCl₃ (3.5 ml) was heated to reflux for48 hr. After the reaction was cooled and concentrated, in vacuo, anethyl acetate solution of the residue was washed with saturated aqueousNaHCO₃ and then brine. The solution was dried (Na₂SO₄), concentrated, invacuo, and then purified on a Biotage™ Flash 12M column using 0-15-30%ethyl acetate in hexanes to afford I-1A-1c as an off-white solid (75 mg,58%): +ESI MS (M+1) 408.0; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.01 (d, J=5.8 Hz,1H), 7.57-7.53 (m, 3H), 7.47 (dd, J=8.7, 2.1 Hz, 1H), 7.41 (d, J=8.7 Hz,2H), 7.27 (d, J=8.7 Hz, 2H).

Preparation of Intermediate1-Benzyl-4-ethylaminopiperidine-4-carbonitrile (I-1A-1d)

To a solution of 4-N-benzylpiperidone (5.69 g, 29.5 mmol) in ethanol(4.2 ml) cooled in an ice bath was added ethylamine hydrochloride (2.69g, 32.3 mmol) in water (3 ml), keeping the internal temperature of thereaction below 10° C. A solution of KCN (2.04 g, 31.3 mmol) in water (7ml) was added to the reaction solution over 10 minutes while keeping theinternal temperature below 10° C. The reaction mixture was then warmedto room temperature and stirred 18 hours. Isopropanol (10 ml) was addedto the reaction mixture to give two distinct layers: lower colorlessaqueous layer and orange organic upper layer. The organic layer wasseparated and stirred with water (30 ml) for 30 minutes. The organiclayer was separated (orange organic layer now the bottom layer), thesolvent was removed in vacuo, and the resultant oil diluted in methylenechloride (30 ml). The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated, in vacuo, to give I-1A-1d as anorange oil (6.05 g, 84%): +APcl MS (M+1) 244.2; ¹H NMR (400 MHz, CD₂Cl₂)δ 7.32 (d, J=4.1 Hz, 4H), 7.29-7.23 (m, 1H), 3.54 (s, 2H), 2.81-2.76 (m,2H), 2.75 (q, J=7.1 Hz, 2H), 2.35-2.29 (m, 2H), 2.01-1.98 (m, 2H),1.74-1.68 (m, 2H), 1.14 (t, J=7.1 Hz, 3H).

Preparation of Intermediate 1-Benzyl-4-ethylaminopiperidine-4-carboxylicAcid Amide (I-1A-1e)

A solution of 1-benzyl-4-ethylaminopiperidine-4-carbonitrile I-1A-1d(0.58 g, 2.38 mmol) in methylene chloride (2 ml) cooled in an ice bathwas treated with H₂SO₄ (1.8 ml, 33 mmol), dropwise, while keeping theinternal temperature below 20° C. The reaction mixture was then warmedto room temperature and stirred for 19 hours. After stirring wasdiscontinued, the thick pale orange H₂SO₄ bottom layer was separated,cooled in an ice bath, and then carefully quenched with concentratedNH₄OH keeping the internal temperature below 55° C. The aqueous layerwas extracted with methylene chloride (2×10 ml), the combined organiclayers were washed with brine (20 ml), dried (Na₂SO₄), and thenconcentrated, in vacuo, to afford I-1A-1e as a pale orange oil thatsolidified to a peach colored solid upon standing (0.54 g, 87%): +APclMS (M+1) 262.2; ¹H NMR (400 MHz, CD₂Cl₂) δ 7.34-7.30 (m, 4H), 7.29-7.21(m, 1H), 7.16 (br s, 1H), 3.48 (s, 2H), 2.71-2.68 (m, 2H), 2.47 (q,J=7.0 Hz, 2H), 2.17-2.02 (m, 4H), 1.62-1.58 (m, 2H), 1.41 (br s, 1H),1.09 (t, J=7.0 Hz, 3H).

Preparation of Intermediate 4-Ethylaminopiperidine-4-carboxylic AcidAmide (I-1A-1f)

To a solution of 1-benzyl-4-ethylaminopiperidine-4-carboxylic acid amide(I-1A-1e; 7.39 g, 28.3 mmol) in methanol (100 ml) was added 20% Pd(OH)₂on carbon (50% water; 1.48 g). The mixture was placed on a Parr® shakerand was reduced (50 psi H₂) at room temperature overnight. The mixturewas filtered through a pad of Celite®, and then concentrated to give acolorless solid I-1A-1f (4.84 g, quantitative): +APcl MS (M+1) 172.2; ¹HNMR (400 MHz, CD₂Cl₂) δ 2.89 (ddd, J=12.9, 8.7, 3.3 Hz, 2H), 2.75 (ddd,J=12.9, 6.6, 3.7 Hz, 2H), 2.45 (q, J=7.2 Hz, 2H), 1.95 (ddd, J=13.7,8.3, 3.7 Hz, 2H), 1.55 (ddd, J=13.7, 6.6, 3.3 Hz, 2h), 1.08 (t, J=7.1Hz, 3H).

Preparation of Intermediate7-Chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-6a)

Intermediate I-1A-6a was prepared by procedures analogous to thosedescribed above for the preparation of7-chloro-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-1c) using appropriate starting materials: +ESI MS (M+1) 374.3; ¹HNMR (400 MHz, CD₂Cl₂) δ 8.00 (d, J=6.2 Hz, 1H), 7.60-7.45 (m, 5H), 7.38(d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H).

Preparation of Intermediate1-Benzhydryl-3-ethylaminoazetidine-3-carboxylic Acid Amide (I-1A-6b)

Oxalyl chloride (145.2 g, 1.121 mol) was added to dichloromethane (3.75liters) and the resulting solution was cooled to −78° C. Dimethylsulfoxide (179.1 g, 2.269 mol) was then added over a duration of 20minutes while maintaining internal temperature of the reaction below−70° C. during addition. 1-Benzhydrylazetidin-3-ol (250.0 g, 1.045 mol)was then added as a solution in dichloromethane (1.25 liter) to the −78°C. solution of DMSO/oxalyl chloride over a duration of 40 minutes(note—internal temperature maintained below −70° C. during addition).The solution was stirred for 1 hour at −78° C. followed by the additionof triethylamine (427.1 g, 4.179 mol) over 30 minutes (maintainedinternal temperature below −70° C. during addition). The reactionmixture was then allowed to come to room temperature slowly and stir for20 hours. 1.0 M hydrochloric acid (3.2 liters, 3.2 mol) was added to thecrude reaction solution over 30 minutes, followed by stirring for 10minutes at room temperature. The heavy dichloromethane layer (clearyellow in color) was then separated and discarded. The remaining acidicaqueous phase (clear, colorless) was treated with 50% sodium hydroxide(150 ml, 2.1 mol) with stirring over a 30-minute period. The finalaqueous solution had a pH=9. At this pH, the desired productprecipitated from solution as a colorless solid. The pH=9 solution wasstirred for 30 minutes and then the precipitated product was collectedby filtration. The collected solid was washed with 1.0 liter of waterand then air dried for 36 hr to give 1-benzhydrylazetidin-3-one (184.1g, 74%) as an off-white solid: +ESI MS (M+1 of hydrated ketone) 256.3;¹H NMR (400 MHz, CD₂Cl₂) δ 7.47-7.49 (m, 4H), 7.27-7.30 (m, 4H),7.18-7.22 (m, 2H), 4.60 (s, 1H), 3.97 (s, 4H).

To a solution of 1-benzhydrylazetidin-3-one (53.4 g, 225 mmol) inmethanol (750 ml) was added ethylamine hydrochloride (20.2 g, 243 mmol),KCN (15.4 g, 229 mmol) and then acetic acid (14.3 ml, 247 mmol) at roomtemperature. After stirring for 2.5 hours at room temperature, at whichpoint the starting ketone had been consumed, the mixture was heated at55° C. for 15 hours. The reaction mixture was cooled to 50° C. andtreated with dimethyl sulfoxide (19.2 ml, 270 mmol) and then 2N aqueousNaOH (251 ml) over a 10-minute period. A solution of 11% aqueousperoxide (80 ml, 247 mmol) was added over 5 minutes (exothermicreaction), during which time a precipitate formed. Additional water (270ml) was added to aid stirring. After the solution was cooled to roomtemperature and stirred for an additional hour, a solid precipitated outof solution and was collected on a sintered funnel, washed with water,and then dried, in vacuo, to give crude I-1A-6b (55.3 g, 79%) as asolid.

For purification purposes, crude1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-2A-1f;83.0 g, 268 mmol) was added to 1 M HCl (1.31), portionwise. Afterwashing the solution with methylene chloride (1 liter, then 0.8 liter),the mixture was treated with 50% aqueous NaOH (130 ml) to bring thepH=10. The precipitate that formed on basification was collected on asintered funnel, washed with water, and then dried, in vacuo, to giveI-1A-6b (72.9 g, 88%) as a colorless solid: +ESI MS (M+1) 310.5; ¹H NMR(400 MHz, CD₃OD) δ 7.41 (d, J=7.1 Hz, 4H), 7.25 (t, J=7.5 Hz, 4H), 7.16(t, J=7.5 Hz, 2H), 4.49 (s, 1H), 3.44 (d, J=8.3 Hz, 2H), 3.11 (d, J=8.3Hz, 2H), 2.47 (q, J=7.1 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H).

Preparation of Intermediate 3-Ethylaminoazetidine-3-carboxylic AcidAmide, Hydrochloride Salt (I-1A-6c)

To a suspension of 1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acidamide (I-1A-6b; 36.1 g, 117 mmol) in methanol (560 ml) at roomtemperature was added concentrated aqueous HCl (19.5 ml, 234 mmol),resulting in a clear solution. To 20% Pd(OH)₂ on carbon (3.75 g) wasadded methanol (85 ml), followed by the methanolic solution of I-1A-6b.The mixture was placed on a Parr® shaker and then reduced (50 psi H₂) atroom temperature for 20 hours. The reaction was then filtered throughCelite® and concentrated to a fraction of the original volume underreduced pressure, at which point a precipitate formed. The suspensionwas diluted with t-butylmethyl ether (MTBE; 500 ml), stirred for anadditional hour, and the precipitate collected by vacuum filtration. Thesolid was washed with MTBE and then dried, in vacuo, to afford I-1A-6c(24.8 g, 98%) as a colorless solid: +APcl MS (M+1) 144.1; ¹H NMR (400MHz, CD₂Cl₂) δ 4.56 (br s, 4H), 3.00 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1Hz, 3H).

Preparation of Intermediate4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid ethyl ester (I-2A-1a)

To a solution of LiN(TMS)₂ (1.0 M in THF, 100 ml, 100 mmol) in 400 mldiethyl ether at −78° C. under nitrogen, 1-(4-chlorophenyl)ethanone(14.3 ml, 110 mmol) in ether (80 ml) was added, dropwise, via additionfunnel. After the addition was complete, the reaction mixture wasstirred at −78° C. for 40 minutes. Oxalic acid diethyl ester (14.3 ml,105 mmol) was added in one portion via syringe. The reaction mixture waswarmed to room temperature and stirred overnight. The pale whiteprecipitate that formed was collected by filtration. The solid was driedin vacuo to give 4-(4-chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acidethyl ester lithium salt (24.0 g, 92%).

4-(4-Chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl ester lithiumsalt (10 g, 38.37 mmol) was dissolved in acetic acid (400 ml). After thesolution was cooled to 10° C. with an ice-water bath, a concentratedaqueous solution of sodium nitrite (2.86 g, 40.29 mmol) was addeddropwise, keeping the temperature between 10 and 15° C. The reactionmixture was stirred for another 45 minutes, and 2-chlorophenylhydrazineHCl salt (8.5 g, 46.04 mmol) was added in portions. Stirring wascontinued for 3 hours. Upon completion of the reaction, the reactionmixture was poured into 600 ml ice-cold water. A yellow solidprecipitated and after 2 hours, it was collected, washed with water, anddried to give crude4-(4-chlorophenyl)-2-[(2-chlorophenyl)hydrazono]-3-nitroso-4-oxobutyricacid ethyl ester which was used in the next step without furtherpurification.

The yellow solid obtained from last step was redissolved intoisopropanol and concentrated H₂SO₄ (1 ml) was added. The reactionmixture was heated to 60° C. for 3 hours. After cooling to roomtemperature, the reaction mixture was poured into ice/saturated aqueousNaHCO₃. The precipitate was formed and collected by filtration and driedto give1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-nitroso-1H-pyrazole-3-carboxylicacid ethyl ester. It was used in the next step without furtherpurification.

1-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-nitroso-1H-pyrazole-3-carboxylicacid ethyl ester obtained from the last step was dissolved in ethylacetate (200 ml) and water (200 ml). Sodium dithionite was added untilthe disappearance of1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-nitroso-1H-pyrazole-3-carboxylicacid ethyl ester was confirmed by TLC (ethyl acetate/hexane, 50/50). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The combined organic layers were dried over magnesiumsulfate and the solvent was removed, in vacuo. The red solid obtainedwas further purified by plug filtration (silica, ethyl acetate/hexane,50/50) to give4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid ethyl ester I-2A-1a (21.86 g, 76%). MS: 376.1 (M+1)⁺.

Preparation of Intermediate3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol(I-2A-1b)

A mixture of4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid ethyl ester I-2A-1a (19.27 g, 51.2 mmol) and formamidine acetate(15.99 g, 153.6 mmol) in 2-ethoxyethanol (100 ml) was refluxed for 3.5 hunder nitrogen. The reaction mixture was then cooled to room temperatureand poured into ice-cold water. The yellow precipitate that formed wascollected by filtration and washed with water. The solid was stirred in45 ml methyl tert-butyl ether for 30 minutes. Cyclohexane (90 ml) wasadded, and the stirring was continued for another 45 minutes. The paleyellow solid was collected by filtration and dried to give3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-olI-2A-1b (17.55 g, 87%): MS: 357.1 (M+1)⁺.

Preparation of Intermediate7-Chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(I-2A-1c)

To a suspension of3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-olI-2A-1b (17.55 g, 49.1 mmol) in 1,2-dichloroethane (109 ml) was addedN,N-diethylaniline (32.8 ml, 206.22 mmol) followed by POCl₃ (70 ml, 0.7M). The reaction mixture was heated to reflux under nitrogen for 3hours, and cooled to room temperature. The solvent was removed underreduced pressure. Excess POCl₃ was removed by co-evaporation withtoluene three times. The residue was dissolved in methylene chloride andslowly poured into vigorously stirred 1:1 CH₂Cl₂/saturated aqueousNaHCO₃ (500 ml). Additional saturated aqueous NaHCO₃ was added until thepH of the mixture was adjusted to neutral. The organic layer wasseparated and the aqueous layer was extracted with 200 ml methylenechloride three times. The organic layers were combined, dried (MgSO₄),and concentrated. The residue was purified by SiO2-gel chromatographyusing 100% CH₂Cl₂ as the eluant to give7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (18.4 g, 76%): MS: 375.0 (M+1)⁺.

Preparation of Intermediate1-Benzhydryl-3-methylaminoazetidine-3-carbonitrile (I-2A-69a)

To a solution of 1-benzhydrylazetidin-3-one (2.13 g, 8.98 mmol) inmethanol (17 ml) was added methylamine hydrochloride (1.21 g, 18.0 mmol)and then acetic acid (1.03 ml, 18.0 mmol) at room temperature. Afterstirring for 5 minutes, solid KCN (1.17 g, 18.0 mmol) was added and themixture was heated to 60° C. for 19 hours. The reaction was cooled; thesolid product was collected by vacuum filtration, rinsed with methanol,and then dried, in vacuo, to afford I-2A-69a as a colorless solid (2.50g, quantitative): +ESI MS (M+1) 278.3; ¹H NMR (400 MHz, CD₂Cl₂) δ 7.43(d, J=7.5 Hz, 4H), 7.29 (t, J=7.5 Hz, 4H), 7.23 (t, J=7.3 Hz, 2H), 4.45(s, 1H), 3.55 (d, J=7.5 Hz, 2H), 3.15 (d, J=7.1 Hz, 2H), 2.40 (s, 3H).

Preparation of Intermediate1-Benzhydryl-3-methylaminoazetidine-3-carboxylic Acid Amide (I-2A-69b)

A vigorously stirred solution of1-benzhydryl-3-methylaminoazetidine-3-carbonitrile (I-2A-69a; 2.10 g,7.57 mmol) in methylene chloride (25 ml) cooled in an ice bath wastreated with H₂SO₄ (4.0 ml, 76 mmol), dropwise. After the reactionmixture was allowed to warm to room temperature and stir overnight, itwas cooled in an ice bath and then carefully quenched with concentratedNH₄OH to pH 11. The mixture was extracted with methylene chloride, thecombined organic layers were dried (Na₂SO₄) and then concentrated, invacuo, to afford I-2A-69b (1.2 g, 54%) as an off-white solid: +ESI MS(M+1) 296.3; ¹H NMR (400 MHz, CD₃OD) δ 7.41 (d, J=7.5 Hz, 4H), 7.25 (t,J=7.5 Hz, 4H), 7.16 (t, J=7.1 Hz, 2H), 4.48 (s, 1H), 3.41 (d, J=8.7 Hz,2H), 3.09 (d, J=8.7 Hz, 2H), 2.24 (s, 3H).

Preparation of Intermediate2-Benzhydryl-5-methyl-2,5,7-triazaspiro[3,4]oct-6-en-8-one (I-2A-69c)

N,N-Dimethylformamide dimethyl acetal (1.1 ml, 8.3 mmol) was combinedwith 1-benzhydryl-3-methylaminoazetidine-3-carboxylic acid amide(I-2A-69b; 153 mg, 0.52 mmol) and heated to reflux. After 3 hours, thesuspension was cooled and extracted from saturated aqueous NaHCO₃ withethyl acetate. The combined extracts were dried (Na₂SO₄), andconcentrated, in vacuo, to afford I-2A-69c as a solid (152 mg, 96%):+ESI MS (M+1) 306.3; ¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.47 (d,J=7.5 Hz, 4H), 7.27 (t, J=7.5 Hz, 4H), 7.17 (t, J=7.5 Hz, 2H), 4.57 (s,1H), 3.58 (s, 3H), 3.55 (d, J=10.0 Hz, 2H), 3.34 (d, J=10.0 Hz, 2H).

Preparation of Intermediate 5-Methyl-2,5,7-triazaspiro[3.4]octan-8-one,Hydrochloride Salt (I-2A-69d)

To a solution of2-benzhydryl-5-methyl-2,5,7-triazaspiro[3,4]oct-6-en-8-one (I-2A-69c;189 mg, 0.619 mmol) in methanol (30 ml) was added 1 M HCl in diethylether (1.3 ml). After the addition of 20% Pd(OH)₂ on carbon (50% water;95 mg), the mixture was placed on a Parr® shaker and then reduced (50psi H₂) at room temperature for 5 hours. The reaction mixture wasfiltered through a 0.45 μM disk, and then concentrated, in vacuo, togive a solid. Trituration from diethyl ether afforded I-2A-69d (124 mg,94%) as an off-white solid: +APcl MS (M+1) 142.0; ¹H NMR (400 MHz,CD₃OD) δ 4.38 (d, J=12.0 Hz, 2H), 4.17 (s, 2H), 4.13 (d, J=12.5 Hz, 2H),2.71 (s, 3H).

Preparation of Intermediate 3-Methylaminoazetidine-3-carboxylic AcidAmide, Hydrochloride Salt (I-2A-90a)

To a suspension of 1-benzhydryl-3-methylaminoazetidine-3-carboxylic acidamide (I-2A-69b; 13.5 g, 45.8 mmol) in methanol (90 ml) was addedconcentrated aqueous HCl (8.0 ml, 96 mol), dropwise, to give ahomogeneous solution. After the addition of 20% Pd(OH)₂ on carbon (50%water; 4.1 g), the mixture was placed on a Parr® shaker and then reduced(50 psi H₂) at room temperature for 7 hours. The mixture was filteredthrough a pad of Celite®, washing with a copious amount of 9:1methanol/water, and then 9:1 tetrahydrofuran/water until no producteluted (determined with ninhydrin stain). The filtrate was thenconcentrated, in vacuo, and the residue was then triturated from diethylether to give I-2A-90a (9.3 g, quantitative) as a brown solid: +APcl MS(M+1) 129.9; ¹H NMR (400 MHz, CD₃OD) δ 4.50 (d, J=12.0 Hz, 2H), 4.43 (d,J=12.9 Hz, 2H), 2.64 (s, 3H).

Preparation of Intermediate1-Benzhydryl-3-benzylaminoazetidine-3-carbonitrile (I-3A-50a)

To a solution of 1-benzhydrylazetidin-3-one (3.3 g, 14 mmol) in methanol(35 ml) was added benzylamine (1.6 ml, 15 mmol) and then acetic acid(0.88 ml, 15 mmol) at room temperature. After stirring for 45 minutes,solid NaCN (0.76 g, 15 mmol) was added in portions over 2 minutes andthe mixture was heated to reflux overnight. The reaction, which nowcontained a precipitate, was cooled and then stirred at roomtemperature. The solids were collected by vacuum filtration, rinsed witha small volume of cold methanol, and then dried, in vacuo, to giveI-3A-50a as a solid (3.56 g, 72%): +APcl MS (M+1) 354.4; ¹H NMR (400MHz, CD₃OD) δ 7.40 (d, J=7.5 Hz, 4H), 7.35 (d, J=7.5 Hz, 2H), 7.31-7.20(m, 7H), 7.16 (t, J=7.3 Hz, 2H), 4.44 (s, 1H), 3.76 (s, 2H), 3.48 (d,J=8.3 Hz, 2H), 3.05 (d, J=8.3 Hz, 2H).

Preparation of Intermediate1-Benzhydryl-3-benzylaminoazetidine-3-carboxylic Acid Amide (I-3A-50b)

A solution of 1-benzhydryl-3-benzylaminoazetidine-3-carbonitrileI-3A-50a (3.45 g, 9.76 mmol) in methylene chloride (55 ml) cooled in anice bath was treated with H₂SO₄ (8.1 ml, 0.15 mol), dropwise. After thereaction mixture was allowed to warm to room temperature and stirovernight, it was cooled in an ice bath and then carefully quenched withconcentrated NH₄OH to pH 10. The mixture was extracted with methylenechloride; the combined organic layers were washed with brine, dried(Na₂SO₄), and then concentrated, in vacuo, to afford a brown solid.Trituration of this material from hexanes/diethyl ether afforded a lighttan solid which was collected by vacuum filtration, washed withadditional hexanes and dried, in vacuo, to give I-3A-50b (3.34 g, 92%):+ESI MS (M+1) 372.4; ¹H NMR (400 MHz, CD₃OD) δ 7.41 (d, J=7.5 Hz, 4H),7.35 (d, J=7.5 Hz, 2H), 7.31-7.22 (m, 7H), 7.16 (t, J=7.7 Hz, 2H), 4.50(s, 1H), 3.60 (s, 2H), 3.48 (d, J=8.3 Hz, 2H), 3.16 (d, J=8.3 Hz, 2H).

Preparation of Intermediate2-Benzhydryl-5-benzyl-2,5,7-triazaspiro[3,4]oct-6-en-8-one (I-3A-50c)

N,N-Dimethylformamide dimethyl acetal (16 ml, 121 mmol) was combinedwith 1-benzhydryl-3-benzylaminoazetidine-3-carboxylic acid amide(I-3A-50b; 3.03 g, 8.16 mmol) and heated to reflux. After 4 hours, thesuspension was cooled and extracted from saturated aqueous NaHCO₃ withethyl acetate. The combined extracts were dried (Na₂SO₄) andconcentrated, in vacuo, to give a crude solid (3.50 g). Purification ofthe residue on a Biotage™ Flash 40M column using 0-3% methanol inmethylene chloride as eluant afforded I-3A-50c as a yellowish solid(1.92 g, 62%): +ESI MS (M+1) 382.3; ¹H NMR (400 MHz, CD₃OD) δ 8.66 (s,1H), 7.59 (d, J=7.1 Hz, 2H), 7.49-7.11 (m, 13H), 5.12 (s, 2H), 4.44 (s,1H), 3.31 (d, J=9.6 Hz, 2H), 3.20 (d, J=9.6 Hz, 2H).

Preparation of Intermediate 2,5,7-Triazaspiro[3,4]octan-8-one,Hydrochloride Salt (I-3A-50d)

To a solution of2-benzhydryl-5-benzyl-2,5,7-triazaspiro[3,4]oct-6-en-8-one (I-3A-50c;1.83 g, 4.80 mmol) in methanol/methylene chloride was added excess 1 MHCl in diethyl ether (10 ml). After stirring for 10 minutes, the solventwas removed, in vacuo, and the resultant hydrochloride salt wasdissolved in methanol (50 ml). After the addition of 20% Pd(OH)₂ oncarbon (50% water; 1.1 g), the mixture was placed on a Parr® shaker andthen reduced (50 psi H₂) at room temperature for 22 hours. The reactionwas filtered through a 0.45 μM disk, and then concentrated, in vacuo, togive a gummy solid. This material was triturated from methanol to affordI-3A-50d (450 mg, 47%) as a tan solid: +APcl MS (M+1) 127.9; ¹H NMR (400MHz, CD₃OD) δ 4.51 (s, 2H), 4.41-4.33 (m, 4H).

Preparation of Intermediate3-(4-Chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-2H-pyrazolo[4,3-d]pyrimidin-7-ol(I-10A-1a)

Potassium t-butoxide (3.0 ml, 1 M in THF; 3.0 mmol) was added to asuspension of propionamidine hydrochloride (326 mg; 3.0 mmol) inethoxyethanol (3 ml). The reaction mixture was immediately concentratedunder vacuum. The residue was re-suspended in ethoxyethanol (3 ml), and4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid ethyl ester I-2A-1a (376 mg, 1 mmol) and glacial acetic acid (250μl; 4.4 mmol) were added. The resulting mixture was heated at 125° C.for 43 hours, cooled to room temperature, quenched with saturatedaqueous NaCl, and extracted with ethyl acetate (2×). The combinedorganic extracts were washed with 0.5 M citric acid, 1 M aqueous K₂CO₃,and saturated aqueous NaCl, dried, and concentrated in vacuo. Theresidue was purified by radial chromatography (4 mm silica gel plate;elution with CH₂Cl₂, followed by 50% hexane/ethyl acetate) to give thedesired product I-10A-1a (7 mg). A solid also precipitated out of thecombined aqueous layers and was collected by filtration to give, afterdrying overnight, additional product (15 mg): MS (M+1)⁺385.4; ¹H NMR(400 MHz, d₆-DMSO) δ 12.05 (s, 1H), 7.78-7.40 (dd, J=7.5, 1.4 Hz, 1H),7.67-7.53 (m, 3H), 7.47-7.42 (m, 2H), 7.39-7.34 (m, 2H), 2.59 (q, J=7.5Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).

Preparation of Intermediate Benzoic Acid 2,2-Difluorobutyl ester(I-10A-6a)

To a solution of benzoic acid 2-oxobutyl ester (20 g, 104 mmol) inCH₂Cl₂ (40 ml) at room temperature was added (diethylamino)sulfurtrifluoride (DAST, 36.9 g, 30 ml, 228.9 mmol) and ethanol (0.4 ml). Thereaction mixture was stirred for 17 hours. Additional DAST (4.5 ml) wasadded dropwise, and the resulting mixture was stirred for 72 hours. Thereaction mixture was quenched first with cold water (250 ml) and thenwith cold saturated aqueous NaHCO₃ (100 ml). The organic layer wasseparated, and the aqueous phase was extracted with CH₂Cl₂ (2×). Thecombined extracts were dried and concentrated under vacuum. The cruderesidue was purified via silica gel chromatography using a solventgradient of 0-2% ethyl acetate/hexanes to give the desired product,benzoic acid 2,2-difluorobutyl ester (I-10A-6a), as a colorless oil: ¹HNMR (400 MHz, CDCl₃) δ 8.05 (d, J=1.2 Hz, 2H), 7.58 (m, 1H), 7.45 (m,2H), 4.48 (t, J=12.0 Hz, 2H), 2.04 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

Preparation of Intermediate 2,2-Difluorobutan-1-ol (I-10A-6b)

A solution of benzoic acid 2,2-difluorobutyl ester (I-10A-6a; 16 g, 75mmol) in 1:1.6 6N aqueous NaOH/methanol (65 ml) was stirred at ambienttemperature for 2 hours. The reaction mixture was concentrated undervacuum to remove the methanolic solvent. The aqueous residue wasextracted with diethyl ether (2×) and the combined ether extracts weredried and concentrated to give the desired product,2,2-difluorobutan-1-ol (I-10A-6b), as a yellow oil contaminated withsome diethyl ether and methanol (6.5 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ3.72 (t, 2H), 1.9 (m, 2H), 1.02 (t, 3H).

Preparation of Intermediate Trifluoromethanesulfonic Acid2,2-Difluorobutyl Ester (I-10A-6c)

A solution of 2,2-difluorobutan-1-ol (I-10A-6b; 1.00 g, 9.1 mmol),N-phenyltrifluoromethanesulfonimide (4.87 g, 13.6 mmol), andtriethylamine (3 ml) in CH₂Cl₂ (15 ml) was stirred at ambienttemperature for 2 hours. The reaction mixture was quenched with 1Naqueous NaOH and extracted with CH₂Cl₂ (3×). The combined organicextracts were washed with saturated aqueous NaCl, dried, andconcentrated under vacuum. The crude residue was purified via silica gelchromatography using a solvent gradient of 10-50% ethyl acetate/hexanesto give the product, trifluoromethanesulfonic acid 2,2-difluoro-butylester (I-10A-6c), as a colorless oil (0.70 g, 32%): ¹H NMR (400 MHz,CDCl₃) δ 4.5 (t, J=11.0 Hz, 2H), 1.95 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

Preparation of Intermediate Benzoic Acid 2,2-Difluoropropyl Ester(I-10A-7a)

The title compound I-10A-7a (47.8 g, 94%) was prepared from benzoic acid2-oxopropyl ester (41.4 g, 232 mmol) using the procedure described abovefor the preparation of I-10A-6a. The crude product was used withoutfurther purification: ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, 2H), 7.58 (m,1H), 7.45 (m, 2H), 4.47 (t, J=12.0 Hz, 2H), 1.73 (t, J=18.7 Hz, 3H).

Preparation of Intermediate 2,2-Difluoropropan-1-ol (1-10A-7b)

A two-phase mixture of benzoic acid 2,2-difluoropropyl ester (I-10A-7a;20 g, 100 mmol) in 1:1.5:2 6N NaOH/H₂O/diethyl ether (183 ml) wasstirred at 50° C. for 17 hours. After cooling to ambient temperature,the reaction mixture was extracted with diethyl ether (3×), and thecombined extracts were dried and concentrated under reduced pressure.The orange-colored crude residue was distilled to give the desiredproduct, 2,2-difluoropropan-1-ol (I-10A-7b), as a colorless oil (2.8 g,29%): boiling point −100° C. (1 atm); ¹H NMR (400 MHz, CDCl₃) δ 3.71 (t,J=12.5 Hz, 2H), 1.64 (t, J=18.7 Hz, 3H).

Preparation of Intermediate Trifluoromethanesulfonic Acid2,2-Difluoropropyl Ester (I-10AA-7c)

To a solution of 2,2-difluoropropan-1-ol (I-10A-7b; 1.76 g, 18.3 mmol),dimethylaminopropylamine (DMAP: 157 mg, 1.3 mmol), and triethylamine(2.20 g, 3.1 ml, 22 mmol) in CH₂Cl₂ (15 ml) at 0° C. was added triflicanhydride (Tf₂O; 6.2 g, 3.7 ml, 22 mmol). The reaction mixture initiallyturned a pink color, then a yellow color following the complete additionof Tf₂O. The reaction mixture was stirred at 0° C. for 2 hours anddiluted with CH₂Cl₂. The organic solution was washed with water, 1 Maqueous citric acid, and saturated aqueous NaHCO₃, dried, andconcentrated under reduced pressure (225 mm/Hg; bath temperature −30°C.) to give the desired product, trifluoromethanesulfonic acid2,2-difluoropropyl ester (I-10A-7c), as a pink oil (3 g, 72%): ¹H NMR(400 MHz, CDCl₃) δ 4.49 (t, J=10.8 Hz, 2H), 1.74 (t, 3H).

Preparation of Intermediate3-(4-Chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-ol(I-10A-14a)

A stirred mixture of7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-6a; 420 mg, 1.12 mmol) in 3M aqueous HCl (7.5 ml) andtetrahydrofuran (12 ml) was heated overnight at 45° C. The reactionmixture was cooled and the pH adjusted to 8 with 5M aqueous NaOH. Theaqueous layer was dried (Na₂SO₄), concentrated, in vacuo, and theresulting solid repulped from 40% ethyl acetate/isopropyl ether (20 ml)to afford I-10A-14a as an off-white solid (320 mg, 80%): +ESI MS (M+1)356.3; ¹H NMR (400 MHz, CD₂Cl₂) δ 9.64 (br s, 1H), 7.55-7.41 (m, 4H),7.34 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.7 Hz, 2H), 6.96 (dd, J=7.5, 5.8 Hz,1H), 6.50 (d, J=7.5 Hz, 1H).

Example 1 Preparation of1-[3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-ethylaminopiperidine-4-carboxylicAcid Amide (1A-1)

7-Chloro-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-1c; 71 mg, 0.17 mmol), 4-ethylaminopiperidine-4-carboxylic acidamide (I-1A-1f; 62 mg, 0.36 mmol) and triethylamine (52 microliters,0.52 mmol) were combined in ethanol (1.2 ml) and the heterogeneousmixture was stirred and heated to 60° C. After 3 days, the reaction wascooled to room temperature and purified on a Biotage™ Flash 12M columnusing a solvent gradient of 0-2-4-6% methanol in methylene chloride aseluant to afford title compound I-1A-1 (73 mg, 78%) as a glass: +ESI MS(M+1) 543.1; ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J=2.1 Hz, 1H), 7.60 (d,J=8.7 Hz, 1H), 7.57 (d, J=6.2 Hz, 1H), 7.49 (dd, J=8.3, 2.1 Hz, 1H),7.38 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 6.84 (d, J=6.2 Hz, 1H),4.35-4.28 (m, 2H), 4.10 (ddd, J=13.3, 9.1, 3.3 Hz, 2H), 2.51 (q, J=7.1Hz, 2H), 2.12 (ddd, J=13.7, 9.1, 3.7 Hz, 2H), 1.73 (dq, J=13.3, 3.3 Hz,2H), 1.10 (t, J=7.1 Hz, 3H).

The hydrochloride Salt of Compound 1A-1 may be Prepared Using theFollowing Procedure:

To a solution of1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide (I-1A-1; 69 mg, 0.13 mmol) in methylene chloride (3 ml) wasadded 1M HCl in diethyl ether (0.32 ml), dropwise. A precipitate formedafter 3 minutes. After stirring for 10 minutes, the ether was removed,in vacuo, the solids were washed with diethyl ether and then dried, invacuo, to afford the hydrochloride salt of 1A-1 as an off-white solid(69 mg, 88%): ¹H NMR (500 MHz, CD₃OD) δ 7.74-7.70 (m, 2H), 7.59 (dd,J=8.7, 2.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.40 (d, J=7.1 Hz, 1H), 7.35(d, J=8.7 Hz, 2H), 7.18 (d, J=7.1 Hz, 1H), 3.08 (q, J=7.2 Hz, 2H),2.76-2.66 (br m, 2H), 2.32 (ddd, J=14.1, 9.6, 4.1 Hz, 2H), 1.37 (t,J=7.3 Hz, 3H).

The compounds listed in Table 1 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 1A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates. The compounds listed below were generally isolatedas their free base and then converted to their correspondinghydrochloride salts prior to in vivo testing. TABLE 1

Example No. —R^(0b) —NRR′ MS (M + H)⁺ IA-2 —Cl

443.1 IA-3 —Cl

472.2 IA-4 —Cl

557.2 IA-5 —Cl

583.2 IA-6 —H

481.4 IA-7 —H

523.5

Example 2 Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[4,3-d]pyrimidine(2A-1)

To a suspension of7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (40 mg, 0.1 mmol) in 5 ml ethanol was added pyrrolidine (711 mg,10 mmol). The reaction mixture was stirred at room temperature for 1hour and became homogeneous. After the reaction was complete (asmonitored by TLC, ethyl acetate/hexane, 50/50), ethanol was removedunder reduced pressure. The residue was redissolved in ethyl acetate,washed with water, dried over magnesium sulfate, and concentrated. Thecrude product was purified by HPLC to give3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[4,3-d]pyrimidine2A-1 (17 mg, 38.2%). MS: 410.2 (M+1)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.3(s, 1H), 7.5 (m, 6H), 7.3 (d, J=8.7 Hz, 2H), 4.2 (t, J=6.3 Hz, 2H), 3.8(t, J=7.1 Hz, 2H), 2.1 (m, 4H).

The compounds listed in Table 2 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 2A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates. The compounds listed below were generally isolatedas their free base and then converted to their correspondinghydrochloride salts prior to in vivo testing. TABLE 2

Example No. R^(0a) R^(0b) —NRR′ MS (M + H)⁺ 2A-2 Cl Cl —N(CH₂CH₃₎ ₂448.2 2A-3 Cl Cl

458.1 2A-4 Cl Cl

460.1 2A-5 Cl Cl

473.2 2A-6 Cl Cl

484.2 2A-7 Cl Cl

446.1 2A-8 Cl H

424.2 2A-9 Cl H

426.2 2A-10 Cl H

439.2 2A-11 Cl H —N(CH₂CH₃)₂ 412.2 2A-12 Cl H

450.2 2A-13 Cl H

464.1 2A-14 Cl H

524.2 2A-15 Cl H

613.2 2A-16 Cl H

539.2 2A-17 Cl H

521.2 2A-18 Cl H

496.1 2A-19 Cl Cl

568.1 2A-20 Cl H

525.2 2A-21 Cl H

481.2 2A-22 Cl H

496.1 2A-23 Cl Cl

555.2 2A-24 Cl H

555.2 2A-25 Cl H

481.1 2A-26 Cl H

516.2 2A-27 Cl H

570.2 2A-28 Cl Cl

488.1 2A-29 Cl H

453.1 2A-30 Cl H

482.1 2A-31 Cl H

570.2 2A-32 Cl Cl

548.2 2A-33 Cl H

451.1 2A-34 Cl H

482.1 2A-35 Cl H

452.2 2A-36 Cl H

530.2 2A-37 Cl Cl

486.1 2A-38 Cl H

492.1 2A-39 Cl H

549.3 2A-40 Cl Cl

512.1 2A-41 Cl H

442.1 2A-42 Cl H

438.1 2A-43 Cl H

452.2 2A-44 Cl H

524.2 2A-45 Cl Cl

517.1 2A-46 Cl H

426.1 2A-47 Cl H

537.2 2A-48 Cl H

507.2 2A-49 Cl H

506.2 2A-50 Cl H

440.1 2A-51 Cl H

484.1 2A-52 Cl H

602.2 2A-53 Cl H

555.2 2A-54 Cl H

440.1 2A-55 Cl H

572.2 2A-56 Cl H

510.2 2A-57 Cl H

438.2 2A-58 Cl H

493.2 2A-59 Cl H

539.2 2A-60 Cl H

517.2 2A-61 Cl H

438.1 2A-62 Cl H

526.2 2A-63 Cl H

492.2 2A-64 Cl Cl

571.1 2A-65 Cl Cl

591.1 2A-66 Cl H

564.0 2A-67 Cl H

550.1 2A-68 Cl H

510.1 2A-69 Cl H

497.0 2A-70 Cl H

480.1 2A-71 Cl Cl —N(CH₂CH₃)₂ 448.2 2A-72 Cl H

454.1 2A-73 Cl Cl

564.0 2A-74 Cl H

536.2 2A-75 Cl H

532.5 2A-76 Cl H

468.2 2A-77 Cl H

482.2 2A-78 Cl H

496.3 2A-79 Cl H

522.3 2A-80 Cl H

538.2 2A-81 Cl H

510.2 2A-82 Cl H

562.2 2A-83 Cl H

494.0 2A-84 Cl H

522.1 2A-85 Cl H

508 2A-86 Cl H

454.3 2A-87 Cl H

454.2 2A-88 Cl H

482.4 2A-89 Cl H

468.3 2A-90 Cl H

440.3 2A-91 Cl H

468.1

Example 3 Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-piperidinyl-1-yl-2H-pyrazolo[4,3-d]pyrimidine(3A-1)

To the mixture of piperidine (102 mg, 1.20 mmol), PS-DIEA(polystyrene-diisopropylethylamine; 130 mg, 3.72 mmol/g) in 1.0 mlethanol was added7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (100 mg, 0.26 mmol). The reaction mixture was shaken for 24hours at 50° C. The PS-DIEA was then filtered off, and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography(silica, 20% ethyl acetate in hexanes grading to 50% ethyl acetate inhexanes). The purified product was dissolved in ethyl acetate (1 ml).HCl in ether (0.2 ml of a 1.0 M solution in diethyl ether) was added,and the precipitate that formed was collected by filtration and dried toprovide3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-piperidinyl-1-yl-2H-pyrazolo[4,3-d]pyrimidine3A-1 (94.4 mg): MS: 423.1 (M+1)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.5 (s,1H), 7.5 (m, 4H), 7.4 (s, 4H), 4.7 (m, 2H), 4.3 (m, 2H), 1.8 (m, 6H).

The compounds listed in Table 3 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 3A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates. The compounds listed below were generally isolatedas their free base and then converted to their correspondinghydrochloride salts prior to in vivo testing. TABLE 3

MS Example No. —NRR′ (M + H)⁺ 3A-2

452.1 3A-3

490.2 3A-4

452.2 3A-5

496.1 3A-6

440.1 3A-7

454.1 3A-8

452.1 3A-9

410.1 3A-10

444.1 3A-11

474.1 3A-12

454.1 3A-13

426.1 3A-14

497.2 3A-15

529.2 3A-16

490.1 3A-17

472.1 3A-18

486.1 3A-19

460.1 3A-20

527.2 3A-21

481.1 3A-22

490.1 3A-23

466.2 3A-24

474.1 3A-25

474.1 3A-26

472.1 3A-27

488.1 3A-28

483.2 3A-29

433.1 3A-30

447.1 3A-31

463.1 3A-32

516.2 3A-33

488.1 3A-34

447.1 3A-35

461.1 3A-36

447.1 3A-37

469.1 3A-38

486.1 3A-39

414.1 3A-40

438.1 3A-41

410.1 3A-42

525.2 3A-43

440.1 3A-44

481.2 3A-45

556.2 3A-46

454.1 3A-47

438.1 3A-48

482.0 3A-49

496.1 3A-50

466.0 3A-51

425.1 3A-52

438.2 3A-53

546.1

Example 4 Preparation ofRac-(S,S)-3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine,Hydrochloride Salt (4A-1):

To the solution of5-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester 2A-46 (595 mg, 1.11 mmol) in dioxane (8 ml) wasadded HCl (2.22 ml, 4 N in dioxane, 8.88 mmol). The reaction mixture wasstirred for 3 hours under nitrogen at room temperature. Then, thereaction mixture was concentrated and co-evaporated with diethyl ether(25 ml). The residue was further dried in a drying pistol under vacuumat 65° C. to giveRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidineHCl salt 4A-1 (522 mg, 92%): MS: 437.1 (M+1)⁺; ¹H NMR (400 MHz, CD₃OD) δ8.6 (d, J=6.2 Hz, 1H), 7.7 (dd, J=15.8, 7.1 Hz, 1H), 7.6 (m, 2H), 7.5(m, 1H), 7.4 (dd, J=8.3, 3.3 Hz, 2H), 7.3 (t, J=7.5 Hz, 2H), 6.3 (s,0.5H), 5.8 (s, 0.5H), 4.7 (m, 1H), 4.6 (d, J=13.7 Hz, 0.5H), 4.5 (dd,J=13.7, 2.5 Hz, 0.5H), 4.2 (ddd, J=29.5, 14.1, 1.7 Hz, 1H), 3.6 (m, 2H),2.5 (dd, J=24.0, 12.0 Hz, 1H), 2.3 (t, J=11.2 Hz, 1H).

The compounds listed in Table 4 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 4A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates. TABLE 4

Example No. —NRR′ MS (M + H)⁺ 4A-2

425.1 4A-3

439.1 4A-4

425.1

Example 5 Preparation ofRac-(S,S)-3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine(5A-1)

To the mixture ofRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidineHCl salt 4A-1 (50.5 mg, 0.1 mmol), triethylammonium chloride (27 mg, 0.2mmol), and triethylamine (0.028 ml, 0.2 mmol) in absolute ethanol (1 ml)was added cyclopentanone (8.8 ml, 0.1 mmol), followed by borohydrideresin (40 mg, 2.5 mmol/g). The mixture was stirred overnight at roomtemperature. After removal of solvent and resin, the residue was furtherpurified by HPLC to giveRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine5A-1 (23 mg, 46%): MS: 504.8 (M+1)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.3 (s,1H), 8.2 (s, 1H), 7.6 (m, 4H), 7.4 (m, 3H), 6.1 (s, 0.5H), 5.4 (s,0.5H), 4.6 (m, 1.5H), 4.3 (m, 0.5H), 4.1 (m, 1H), 3.7 (m, 3H), 2.4 (m,2H), 2.3 (m, 1H), 2.2 (m, 1H), 1.8 (m, 2H), 1.6 (m, 4H).

The compounds listed in Table 5 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 5A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates. The compounds listed below were generally isolatedas their free base and then converted to their correspondinghydrochloride salts prior to in vivo testing. TABLE 5

Example No. —NRR′ MS (M + H)⁺ 5A-2

493.0 5A-3

493.1 5A-4

479.1 5A-5

466.8 5A-6

519.1 5A-7

465.1 5A-8

493.1 5A-9

507.1 5A-10

481.1

Example 6 Preparation ofRac-(S,S)-3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine(6A-1)

A solution ofRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine4A-1 (63 mg, 0.12 mmol) in dichloromethane (2 ml) was charged withtriethylamine (0.1 ml). Methanesulfonyl chloride (0.01 ml, 0.14 mmol)was added via syringe, and the resultant mixture was stirred at 23° C.for 3 days. The reaction mixture was then washed with water (2 ml) andthe layers were separated. The organic solution was dried over anhydrousmagnesium sulfate and concentrated. Purification of the residue byreverse-phase HPLC affordedRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine6A-1 (63 mg, quantitative): MS: 515.0 (M+1)⁺; ¹H NMR (400 MHz, CD₃OD) δ8.3 (s, 0.5H), 8.1 (s, 0.5H), 7.6 (m, 4H), 7.4 (m, 4H), 6.1 (s, 0.5H),5.2 (s, 0.5H), 4.7 (m, 1H), 4.4 (m, 0.5H), 4.2 (m, 0.5H), 4.0 (m, 1H),3.8 (m, 1H), 3.5 (m, 3H), 3.0 (s, 3H).

The compounds listed in Table 6 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 6A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogues to routes described above forother intermediates. The compounds listed below were generally isolatedas their free base and then converted to their correspondinghydrochloride salts prior to in vivo testing. TABLE 6

Example No. —NRR′ MS (M + H)⁺ 6A-2

515.0 6A-3

544.2 6A-4

532.2 6A-5

582.9 6A-6

503.2 6A-7

531.2 6A-8

517.2 6A-9

571.1

Example 7 Preparation of7-(1-Benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(7A-1)

Sodium hydride (24 mg of a 60% dispersion in mineral oil, 0.6 mmol) wasadded to a solution of 1-benzylpyrrolidin-3-ol (0.1 ml, 0.6 mmol) indimethylformamide (1 ml), and the resultant mixture was stirred at roomtemperature for 5 min. Next,7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (50 mg, 0.13 mmol) was added in one portion, and the mixture wasstirred for 2 hours. The reaction mixture was diluted with methyltert-butyl ether and washed with water (3×). The organic phase was driedover anhydrous magnesium sulfate and concentrated. Purification of theresidue by flash column chromatography (50% ethyl acetate in hexanes)provided the title compound7-(1-benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine7A-1 (21 mg): MS: 516.1 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.6 (s, 1H),7.5 (m, 6H), 7.3 (m, 7H), 5.8 (m, 1H), 3.7 (s, 2H), 3.2 (m, 1H), 2.9 (m,1H), 2.8 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.2 (m, 1H).

Example 8 Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine(8A-1)

Sodium (21 mg, 0.9 mmol) was added to 2-propanol (2 ml), and theresultant mixture was stirred at 65° C. for 16 hours. Next,7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (75 mg, 0.2 mmol) was added in one portion, and the mixture wasstirred at 65° C. for 2 hours. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was dried overanhydrous magnesium sulfate and concentrated. Purification of theresidue by flash column chromatography (50% ethyl acetate in hexanes)provided the title compound3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine8A-1 (41 mg): MS: 399.1 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.6 (s, 1H),7.6 (d, J=6.6 Hz, 1H), 7.5 (m, 5H), 7.3 (d, J=8.7 Hz, 2H), 5.8(pentuplet, J=6.2 Hz, 1H), 1.5 (d, J=6.2 Hz, 6H).

Example 9 Preparation of7-(1-Benzhydrylazetidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(9A-1)

A solution of7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(I-2A-1c; 50 mg, 0.13 mmol), 1,4-diazabicyclo[2.2.2]octane (DABCO, 15mg, 0.13 mmol), and triethylamine (0.054 ml, 0.39 mmol) in1,2-dichloroethane (1 ml) was stirred for 16 hours. The reaction mixturewas diluted with dichloromethane and washed with water. The organicswere dried over anhydrous magnesium sulfate and were concentrated.Purification of the residue by flash column chromatography (20% ethylacetate in hexanes) provided the title compound7-(1-benzhydrylazetidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine9A-1 (32 mg): ¹H NMR (400 MHz, CDCl₃) δ 8.6 (s, 1H), 7.4 (complex, 18H),5.6 (m, 1H), 4.5 (br s, 1H), 3.8 (br s, 2H), 3.3 (br s, 2H).

Example 10 Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one(10A-1)

A mixture of3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-2H-pyrazolo[4,3-d]pyrimidin-7-ol(I-10A-1a; 15 mg, 0.039 mmol), Cs₂CO₃ (52 mg, 0.16 mmol) and CF₃CH₂I (39microliters, 0.4 mmol) in dimethylformamide (1 ml) was stirred at 100°C. for 18 hours. The reaction mixture was cooled to room temperature,quenched with saturated aqueous sodium chloride, and extracted withethyl acetate (2×). The combined extracts were washed with saturatedaqueous NaCl, dried over Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by radial chromatography (1 mm silica gelplate; solvent gradient of 25-50% ethyl acetate/hexane) to provide thedesired product,3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one10A-1 (4 mg): MS (M+1)⁺467.4; ¹H NMR (400 MHz, CD₂Cl₂) δ 7.59-7.46 (m,6H), 7.37-7.33 (m, 2H), 4.35 (br m, 2H), 3.04 (q, J=7.4 Hz, 2H), 1.40(t, J=7.4 Hz, 3H).

The compounds listed in Table 7 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 10A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates. Examples 10A-12, 10A-13 and 10A-14 were alkylatedat room temperature. TABLE 7

Example MS No. A —R^(0a) —R^(0b) —R^(1a) —R³ —R⁴ (M + 1) 10A-2 N —Cl —H—Cl —i-Pr —OCH₂CF₃ 481.4 10A-3 N —Cl —H —OMe —Me —OCH₂CF₃ 449.4 10A-4 N—Cl —H —Cl —CF₃ —OCH₂CH₃ 453.3 10A-5 N —Cl —H —Cl —CF₃ —OCH₂CF₃ 507.110A-6 N —Cl —H —Cl —Me —OCH₂CF₂CH₂CH₃ 463.4 10A-7 N —Br —H —Cl —Me—OCH₂CF₂CH₃ 492.9 10A-8 N —Br —H —OMe —Me —OCH₂CF₃ 493.0 10A-9 N —Br —H—OMe —Me —OCH₂CF₂CH₃ 489.0 10A-10 N —Cl —H —Br —Me —OCH₂CF₂CH₃ 492.810A-11 N —Cl —H —OMe —Me —OCH₂CF₂CH₃ 445.1 10A-12 N —Cl —H —CF₃ —H—OCH(CH₃)₂ 433.4 10A-13 N —Cl —Me —CF₃ —Me —OCH₂CF₃ 501.5 10A-14 CH —Cl—H —Cl —H —OCH₂CF₃ 438.3Me = —CH₃;i-Pr = CH(CH₃)₂

Example 11 Preparation of2-[3-(4-Chlorophenyl)-7-(2,2-difluopropoxy)-5-methyl-pyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile(11A-1)

A mixture of2-(2-bromophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine(10A-7, 50 mg, 0.1 mmol), Zn(CN)₂ (20 mg, 0.17 mmol), Pd(PPh₃)₄ (15 mg,0.01 mmol) in DMF (1 ml) was heated in a microwave apparatus (EmrysOptimizer, Personal Chemistry) at 200° C. for 3 minutes. The reactionmixture was quenched with saturated aqueous NaCl and extracted withethyl acetate (2×). The combined organic extracts were dried andconcentrated under vacuum. The crude residue was purified via HPLC(Shimadzu) using a solvent gradient of 30% CH₃CN/hexanes to 100% CH₃CNto give the desired product,2-[3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methylpyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile(11A-1), as a colorless solid (25 mg): MS (M+1)⁺440.0; ¹H NMR (400 MHz,CDCl₃) δ 7.80-7.64 (m, 4H), 7.40-7.26 (m, 4H), 4.8 (t, J=11.6 Hz, 2H),2.7 (s, 3H), 1.79 (t, J=18.67 Hz, 3H).

Example 12 Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-ethoxy-2H-pyrazolo[4,3-d]pyrimidine(12A-1)

To a solution of7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(I-2A-1c; 50 mg, 0.133 mmol) and ethanol (0.016 ml, 0.27 mmol) intetrahydrofuran (1.5 ml) was added NaH (60% dispersion in oil, 14 mg,0.33 mmol). After stirring for 1 hour, the reaction was extracted fromsaturated aqueous NaHCO₃ with ethyl acetate, the combined organic layerswere dried (MgSO₄), concentrated and purified on a Biotage™ Flash 12Mcolumn using a solvent gradient of 0-20% ethyl acetate in hexanes aseluant to afford 12A-1 (46 mg, 92%) as a colorless solid: +ESI MS (M+1)385.4; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.56 (s, 1H), 7.58-7.46 (m, 6H), 7.34(d, J=8.7 Hz, 2H), 4.70 (q, J=7.1 Hz, 2H), 1.53 (t, J=7.1 Hz, 3H).

The compounds listed in Table 8 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 12A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates. TABLE 8

Example No. A —R MS (M + H)⁺ 12A-2 N —OCH₂CH₂CH₃ 399.4 12A-3 N—OCH₂CH₂CH₂CH₃ 413.4 12A-4 CH —OCH(CH₃)₂ 398.4

Pharmacological Testing

The utility of the compounds of the present invention in the practice ofthe instant invention can be evidenced by activity in at least one ofthe protocols described hereinbelow. The following acronyms are used inthe protocols described below.

BSA—bovine serum albumin

DMSO—dimethylsulfoxide

EDTA—ethylenediamine tetracetic acid

PBS—phosphate-buffered saline

EGTA—ethylene glycol-bis(β-aminoethyl ether) N,N,N′,N′-tetraacetic acid

GDP—guanosine diphosphate

sc—subcutaneous

po—orally

ip—intraperitoneal

icv—intra cerebro ventricular

iv—intravenous

[³H]SR141716A—radiolabeledN-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride available from Amersham Biosciences, Piscataway, N.J.

[³H]CP-55940—radiolabled5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)-cyclohexyl]-phenolavailable from NEN Life Science Products, Boston, Mass.

AM251—N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamideavailable from Tocris™, Ellisville, Mo.

All of the compounds listed in the Example section above were tested inthe CB-1 receptor binding assay below. The compounds provided a range ofbinding activities from 0.2 nM to 1.6 μM. The compounds having anactivity <20 nM were then tested in the CB-1 GTPγ [³⁵S] Binding Assayand the CB-2 binding assay described below in the Biological BindingAssays section. Selected compounds were then tested in vivo using one ormore of the functional assays described in the Biological FunctionalAssays section below.

In Vitro Biological Assays

Bioassay systems for determining the CB-1 and CB-2 receptor bindingproperties and pharmacological activity of cannabinoid receptor ligandsare described by Roger G. Pertwee in “Pharmacology of CannabinoidReceptor Ligands” Current Medicinal Chemistry, 6, 635-664 (1999) and inWO 92/02640 (U.S. application Ser. No. 07/564,075 filed Aug. 8, 1990,incorporated herein by reference).

The following assays were designed to detect compounds that inhibit thebinding of [³H]-SR141716A (selective radiolabeled CB-1 receptor ligand)and[³H]-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)-cyclohexyl]-phenol;radiolabeled CB-1/CB-2 receptor ligand) to their respective receptors.

Rat CB-1 ReceDtor Binding Protocol

PelFreeze brains (available from Pel Freeze Biologicals, Rogers, Ark.)were cut up and placed in tissue preparation buffer (5 mM Tris HCl,pH=7.4 and 2 mM EDTA), polytroned at high speed and kept on ice for 15minutes. The homogenate was then spun at 1,000×g for 5 minutes at 4° C.The supernatant was recovered and centrifuged at 100,000×G for 1 hour at4° C. The pellet was then re-suspended in 25 ml of TME (25 nM Tris,pH=7.4, 5 mM MgCl₂, and 1 mM EDTA) per brain used. A protein assay wasperformed and 200 μl of tissue totaling 20 μg was added to the assay.

The test compounds were diluted in drug buffer (0.5% BSA, 10% DMSO andTME) and then 25 μl were added to a deep well polypropylene plate.[³H]-SR141716A was diluted in a ligand buffer (0.5% BSA plus TME) and 25μl were added to the plate. A BCA protein assay was used to determinethe appropriate tissue concentration and then 200 μl of rat brain tissueat the appropriate concentration was added to the plate. The plates werecovered and placed in an incubator at 20° C. for 60 minutes. At the endof the incubation period 250 μl of stop buffer (5% BSA plus TME) wasadded to the reaction plate. The plates were then harvested by Skatrononto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME. Each filterwas washed twice. The filters were dried overnight. In the morning thefilters were counted on a Wallac Betaplate™ counter (available fromPerkinElmer Life Sciences™, Boston, Mass.).

Human CB-1 Receptor Binding Protocol

Human embryonic kidney 293 (HEK 293) cells transfected with the CB-1receptor cDNA (obtained from Dr. Debra Kendall, University ofConnecticut) were harvested in homogenization buffer (10 mM EDTA, 10 mMEGTA, 10 mM Na Bicarbonate, protease inhibitors; pH=7.4), andhomogenized with a Dounce Homogenizer. The homogenate was then spun at1,000×G for 5 minutes at 4° C. The supernatant was recovered andcentrifuged at 25,000×G for 20 minutes at 4° C. The pellet was thenre-suspended in 10 ml of homogenization buffer and re-spun at 25,000×Gfor 20 minutes at 4° C. The final pellet was re-suspended in 1 ml of TME(25 mM Tris buffer (pH=7.4) containing 5 mM MgCl₂ and 1 mM EDTA). Aprotein assay was performed and 200 μl of tissue totaling 20 μg wasadded to the assay.

The test compounds were diluted in drug buffer (0.5% BSA, 10% DMSO andTME) and then 25 μl were added to a deep well polypropylene plate.[³H]-SR141716A was diluted in a ligand buffer (0.5% BSA plus TME) and 25μl were added to the plate. The plates were covered and placed in anincubator at 30° C. for 60 minutes. At the end of the incubation period250 A1 of stop buffer (5% BSA plus TME) was added to the reaction plate.The plates were then harvested by Skatron onto GF/B filtermats presoakedin BSA (5 mg/ml) plus TME. Each filter was washed twice. The filterswere dried overnight. In the morning, the filters were counted on aWallac Betaplate™ counter (available from PerkinElmer Life Sciences™,Boston, Mass.).

CB-2 Receptor Binding Protocol

Chinese hamster ovary-K1 (CHO-K1) cells transfected with CB-2 receptorcDNA (obtained from Dr. Debra Kendall, University of Connecticut) wereharvested in tissue preparation buffer (5 mM Tris-HCl buffer (pH=7.4)containing 2 mM EDTA), polytroned at high speed and kept on ice for 15minutes. The homogenate was then spun at 1,000×G for 5 minutes at 4° C.The supernatant was recovered and centrifuged at 100,000×G for 1 hour at4° C. The pellet was then re-suspended in 25 ml of TME (25 mM Trisbuffer (pH=7.4) containing 5 mM MgCl₂ and 1 mM EDTA) per brain used. Aprotein assay was performed and 200 μl of tissue totaling 10 fig wasadded to the assay.

The test compounds were diluted in drug buffer (0.5% BSA, 10% DMSO, and80.5% TME) and then 25 μl were added to the deep well polypropyleneplate.[³H]-5-(1,1-Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenolwas diluted a ligand buffer (0.5% BSA and 99.5% TME) and then 25 pt wereadded to each well at a concentration of 1 nM. A BCA protein assay wasused to determine the appropriate tissue concentration and 200 μl of thetissue at the appropriate concentration was added to the plate. Theplates were covered and placed in an incubator at 30° C. for 60 minutes.At the end of the incubation period 250 μl of stop buffer (5% BSA plusTME) was added to the reaction plate. The plates were then harvested bySkatron format onto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME.Each filter was washed twice. The filters were dried overnight. Thefilters were then counted on the Wallac Betaplate™ counter.

CB-1 Receptor GTPγ [³⁵S] Binding Assay

Membranes were prepared from CHO-K1 cells stably transfected with thehuman CB-1 receptor cDNA. Membranes were prepared from cells asdescribed by Bass et al., in “Identification and characterization ofnovel somatostatin antagonists,” Molecular Pharmacology, 50, 709-715(1996). GTPγ [³⁵S] binding assays were performed in a 96 wellFlashPlate™ format in duplicate using 100 μM GTPγ [³⁵S] and 10 μgmembrane per well in assay buffer composed of 50 mM Tris HCl, pH 7.4, 3mM MgCl₂, pH 7.4, 10 mM MgCl₂, 20 mM EGTA, 100 mM NaCl, 30 μM GDP, 0.1%bovine serum albumin and the following protease inhibitors: 100 μg/mlbacitracin, 100 μg/ml benzamidine, 5 μg/ml aprotinin, 5 μg/ml leupeptin.The assay mix was then incubated with increasing concentrations ofantagonist (10⁻¹⁰ M to 10⁻⁵ M) for 10 minutes and challenged with thecannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(10 μM). Assays were performed at 30° C. for one hour. The FlashPlates™were then centrifuged at 2000×G for 10 minutes. Stimulation of GTPγ [3S]binding was then quantified using a Wallac Microbeta. EC₅₀ calculationsdone using Prism™ by Graphpad.

Inverse agonism was measured in the absense of agonist.

CB-1 ReceDtor FLIPR-Based Functional Assay Protocol

CHO-K1 cells co-transfected with the human CB-1 receptor cDNA (obtainedfrom Dr. Debra Kendall, University of Connecticut) and the promiscuousG-protein G16 were used for this assay. Cells were plated 48 hours inadvance at 12500 cells per well on collagen coated 384 well black clearassay plates. Cells were incubated for one hour with 4 μM Fluo-4 μM(Molecular Probes) in DMEM (Gibco) containing 2.5 mM probenicid andpluronic acid (0.04%). The plates were then washed 3 times withHEPES-buffered saline (containing probenicid; 2.5 mM) to remove excessdye. After 20 min the plates were added to the FLIPR individually andfluorescence levels was continuously monitored over an 80 second period.Compound additions were made simultaneously to all 384 wells after 20seconds of baseline. Assays were performed in triplicate and 6 pointconcentration-response curves generated. Antagonist compounds weresubsequently challenged with 3 μM WIN 55,212-2 (agonist). Data wereanalyzed using Graph Pad Prism.

Detection of Inverse Agonists

The following cyclic-AMP assay protocol using intact cells was used todetermine inverse agonist activity.

Cells were plated into a 96-well plate at a plating density of10,000-14,000 cells per well at a concentration of 100 μl per well. Theplates were incubated for 24 hours in a 37° C. incubator. The media wasremoved and media lacking serum (100 μl) was added. The plates were thenincubated for 18 hours at 37° C.

Serum free medium containing 1 mM IBMX was added to each well followedby 10 μl of test compound (1:10 stock solution (25 mM compound in DMSO)into 50% DMSO/PBS) diluted 10× in PBS with 0.1% BSA. After incubatingfor 20 minutes at 37° C., 2 LM of forskolin was added and then incubatedfor an additional 20 minutes at 37° C. The media was removed, 100 μl of0.01N HCl was added and then incubated for 20 minutes at roomtemperature. Cell lysate (75 μl) along with 25 μl of assay buffer(supplied in FlashPlate™ cAMP assay kit available from NEN Life ScienceProducts Boston, Mass.) into a Flashplate. cAMP standards and cAMPtracer were added following the kit's protocol. The flashplate was thenincubated for 18 hours at 4° C. The content of the wells were aspiratedand counted in a Scintillation counter.

In Vivo Biological Assays

Cannabinoid agonists such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenolhave been shown to affect four characteristic behaviors in mice,collectively known as the Tetrad. For a description of these behaviorssee: Smith, P. B., et al. in “The pharmacological activity ofanandamide, a putative endogenous cannabinoid, in mice.” J. Pharmacol.Exp. Ther., 270(1), 219-227 (1994) and Wiley, J., et al. in“Discriminative stimulus effects of anandamide in rats,” Eur. J.Pharmacol., 276(1-2), 49-54 (1995). Reversal of these activities in thelocomotor activity, catalepsy, hypothermia, and hot plate assaysdescribed below provides a screen for in vivo activity of CB-1 receptorantagonists.

All data is presented as % reversal from agonist alone using thefollowing formula:(5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol/agonist-vehicle/agonist)/(vehicle/vehicle-vehicle/agonist).Negative numbers indicate a potentiation of the agonist activity ornon-antagonist activity. Positive numbers indicate a reversal ofactivity for that particular test.

Locomotor Activity

Male ICR mice (n=6; 17-19 g, Charles River Laboratories, Inc.,Wilmington, Mass.) were pre-treated with test compound (sc, po, ip, oricv). Fifteen minutes later, the mice were challenged with5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Twenty-five minutes after the agonist injection, the mice wereplaced in clear acrylic cages (431.8 cm×20.9 cm×20.3 cm) containingclean wood shavings. The subjects were allowed to explore surroundingsfor a total of about 5 minutes and the activity was recorded by infraredmotion detectors (available from Coulbourn Instruments™, Allentown, Pa.)that were placed on top of the cages. The data was computer collectedand expressed as “movement units.”

Catalepsy

Male ICR mice (n=6; 17-19 g upon arrival) were pre-treated with testcompound (sc, po, ip or icv). Fifteen minutes later, the mice werechallenged with5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Ninety minutes post injection, the mice were placed on a 6.5 cmsteel ring attached to a ring stand at a height of about 12 inches. Thering was mounted in a horizontal orientation and the mouse was suspendedin the gap of the ring with fore- and hind-paws gripping the perimeter.The duration that the mouse remained completely motionless (except forrespiratory movements) was recorded over a 3-minute period.

The data were presented as a percent immobility rating. The rating wascalculated by dividing the number of seconds the mouse remainsmotionless by the total time of the observation period and multiplyingthe result by 100. A percent reversal from the agonist was thencalculated.

Hypothermia

Male ICR mice (n=5; 17-19 g upon arrival) were pretreated with testcompounds (sc, po, ip or icv). Fifteen minutes later, mice werechallenged with the cannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Sixty-five minutes post agonist injection, rectal bodytemperatures were taken. This was done by inserting a small thermostatprobe approximately 2-2.5 cm into the rectum. Temperatures were recordedto the nearest tenth of a degree

Hot Plate

Male ICR mice (n=7; 17-19 g upon arrival) are pre-treated with testcompounds (sc, po, ip or iv). Fifteen minutes later, mice werechallenged with a cannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Forty-five minutes later, each mouse was tested for reversal ofanalgesia using a standard hot plate meter (Columbus Instruments). Thehot plate was 10″×10″×0.75″ with a surrounding clear acrylic wall.Latency to kick, lick or flick hindpaw or jump from the platform wasrecorded to the nearest tenth of a second. The timer was experimenteractivated and each test had a 40 second cut off. Data were presented asa percent reversal of the agonist induced analgesia.

Food Intake

The following screen was used to evaluate the efficacy of test compoundsfor inhibiting food intake in Sprague-Dawley rats after an overnightfast.

Male Sprague-Dawley rats were obtained from Charles River Laboratories,Inc. (Wilmington, Mass.). The rats were individually housed and fedpowdered chow. They were maintained on a 12-hour light/dark cycle andreceived food and water ad libitum. The animals were acclimated to thevivarium for a period of one week before testing was conducted. Testingwas completed during the light portion of the cycle.

To conduct the food intake efficacy screen, rats were transferred toindividual test cages without food the afternoon prior to testing, andthe rats were fasted overnight. After the overnight fast, rats weredosed the following morning with vehicle or test compounds. A knownantagonist was dosed (3 mg/kg) as a positive control, and a controlgroup received vehicle alone (no compound). The test compounds weredosed at ranges between 0.1 and 100 mg/kg depending upon the compound.The standard vehicle was 0.5% (w/v) methylcellulose in water and thestandard route of administration was oral. However, different vehiclesand routes of administration were used to accommodate various compoundswhen required. Food was provided to the rats 30 minutes after dosing andthe Oxymax automated food intake system (Columbus Instruments, Columbus,Ohio) was started. Individual rat food intake was recorded continuouslyat 10-minute intervals for a period of two hours. When required, foodintake was recorded manually using an electronic scale; food was weighedevery 30 minutes after food was provided up to four hours after food wasprovided. Compound efficacy was determined by comparing the food intakepattern of compound-treated rats to vehicle and the standard positivecontrol.

Alcohol Intake

The following protocol evaluates the effects of alcohol intake inalcohol preferring (P) female rats (bred at Indiana University) with anextensive drinking history. The following references provide detaileddescriptions of P rats: Li T.-K., et al., “Indiana selection studies onalcohol related behaviors” in Development of Animal Models asPharmacogenetic Tools (eds McClearn C. E., Deitrich R. A. and Erwin V.G.), Research Monograph 6, 171-192 (1981) NIAAA, ADAMHA, Rockville, Md.;Lumeng, L, et al., “New strains of rats with alcohol preference andnonpreference” Alcohol And Aldehyde Metabolizing Systems, 3, AcademicPress, New York, 537-544 (1977); and Lumeng, L, et al., “Differentsensitivities to ethanol in alcohol-preferring and -nonpreferring rats,”Pharmacol, Biochem Behav., 16, 125-130 (1982).

Female rats were given 2 hours of access to alcohol (10% v/v and water,2-bottle choice) daily at the onset of the dark cycle. The rats weremaintained on a reverse cycle to facilitate experimenter interactions.The animals were initially assigned to four groups equated for alcoholintakes: Group 1—vehicle (n=8); Group 2—positive control (e.g. 5.6 mg/kgAM251; n=8); Group 3—low dose test compound (n=8); and Group 4—high doseof test compound (n=8). Test compounds were generally mixed into avehicle of 30% (w/v) β-cyclodextrin in distilled water at a volume of1-2 ml/kg. Vehicle injections were given to all groups for the first twodays of the experiment. This was followed by 2 days of drug injections(to the appropriate groups) and a final day of vehicle injections. Onthe drug injection days, drugs were given sc 30 minutes prior to a2-hour alcohol access period. Alcohol intake for all animals wasmeasured during the test period and a comparison was made between drugand vehicle-treated animals to determine effects of the compounds onalcohol drinking behavior.

Additional drinking studies were done utilizing female C57BL/6 mice(Charles River). Several studies have shown that this strain of micewill readily consume alcohol with little to no manipulation required(Middaugh et al., “Ethanol Consumption by C57BL/6 Mice: Influence ofGender and Procedural Variables” Alcohol, 17 (3), 175-183, 1999; Le etal., “Alcohol Consumption by C57BU6, BALA/c, and DBA/2 Mice in a LimitedAccess Paradigm” Pharmacology Biochemisrty and Behavior, 47, 375-378,1994).

For our purposes, upon arrival (17-19 g) mice were individually housedand given unlimited access to powdered rat chow, water and a 10% (w/v)alcohol solution. After 2-3 weeks of unlimited access, water wasrestricted for 20 hours and alcohol was restricted to only 2 hoursaccess daily. This was done in a manner that the access period was thelast 2 hours of the dark part of the light cycle.

Once drinking behavior stabilized, testing commenced. Mice wereconsidered stable when the average alcohol consumption for 3 days was+20% of the average for all 3 days. Day 1 of test consisted of all micereceiving vehicle injection (sc or ip). Thirty to 120 minutes postinjection access was given to alcohol and water. Alcohol consumption forthat day was calculated (g/kg) and groups were assigned (n=7-10) so thatall groups had equivocal alcohol intake. On day 2 and 3, mice wereinjected with vehicle or drug and the same protocol as the previous daywas followed. Day 4 was wash out and no injections were given. Data wasanalyzed using repeated measures ANOVA. Change in water or alcoholconsumption was compared back to vehicle for each day of the test.Positive results would be interpreted as a compound that was able tosignificantly reduce alcohol consumption while having no effect on water

Oxygen Consumption

Methods:

Whole body oxygen consumption was measured using an indirect calorimeter(Oxymax from Columbus Instruments, Columbus, Ohio) in male SpragueDawley rats (if another rat strain or female rats are used, it will bespecified). Rats (300-380 g body weight) were placed in the calorimeterchambers and the chambers were placed in activity monitors. Thesestudies were done during the light cycle. Prior to the measurement ofoxygen consumption, the rats were fed standard chow ad libitum. Duringthe measurement of oxygen consumption, food was not available. Basalpre-dose oxygen consumption and ambulatory activity were measured every10 minutes for 2.5 to 3 hours. At the end of the basal pre-dosingperiod, the chambers were opened and the animals were administered asingle dose of compound (the usual dose range is 0.001 to 10 mg/kg) byoral gavage (or other route of administration as specified, i.e., sc,ip, iv). Drugs were prepared in methylcellulose, water or otherspecified vehicle (examples include PEG400, 30% beta-cyclo dextran andpropylene glycol). Oxygen consumption and ambulatory activity weremeasured every 10 minutes for an additional 1-6 hours post-dosing.

The Oxymax calorimeter software calculated the oxygen consumption(ml/kg/h) based on the flow rate of air through the chambers anddifference in oxygen content at inlet and output ports. The activitymonitors have 15 infrared light beams spaced one inch apart on eachaxis, ambulatory activity was recorded when two consecutive beams arebroken and the results are recorded as counts.

Resting oxygen consumption, during pre- and post-dosing, was calculatedby averaging the 10-minute O₂ consumption values, excluding periods ofhigh ambulatory activity (ambulatory activity count>100) and excludingthe first 5 values of the pre-dose period and the first value from thepost-dose period. Change in oxygen consumption was reported as percentand was calculated by dividing the post-dosing resting oxygenconsumption by the pre-dose oxygen consumption* 100. Experiments wouldtypically be done with n=4-6 rats and results reported are mean +/−SEM.

Interpretation:

An increase in oxygen consumption of >10% was considered a positiveresult. Historically, vehicle-treated rats have no change in oxygenconsumption from pre-dose basal.

1. A compound of Formula (I)

wherein A is C(R²), where R² is hydrogen, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl, or (C₁-C₄)alkoxy; R⁰ is an optionally substituted aryl oran optionally substituted heteroaryl; R¹ is an optionally substitutedaryl or an optionally substituted heteroaryl; R³ is hydrogen,(C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or (C₁-C₄)alkoxy; R⁴ is (i)a group having Formula (IA) or Formula (IB)

where R^(4a′) is hydrogen or (C₁-C₃)alkyl; R^(4b) and R^(4b′) are eachindependently hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or either R^(4b) or R^(4b′)taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are each independentlyhydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda 3-6 membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, oreither R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge or an ethylene bridge; Y isoxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) andR^(4d′) are each independently hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, orR^(4d) and R^(4c′) taken together form a 3-6 membered partially or fullysaturated carbocyclic ring, 3-6 membered partially or fully saturatedheterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactamring, where said carbocyclic ring, said heterocyclic ring, said lactonering and said lactam ring are optionally substituted with one or moresubstituents and said lactone ring and said lactam ring optionallycontain an additional heteroatom selected from oxygen, nitrogen orsulfur, or Y is —NR^(4d) where R^(4d″) is a hydrogen or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, whereR^(4e) and R^(4e′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, oreither R^(4e) or R^(4e′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; andR^(4f) and R^(4f′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, oreither R^(4f) or R^(4f′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; (ii) agroup having Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl, or (C₁-C₄)alkyl,and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or an optionallysubstituted 4-6 membered partially or fully saturated heterocylic ringcontaining 1 to 2 heteroatoms independently selected from oxygen, sulfuror nitrogen, or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6membered lactone, 4-6 membered lactam, or a 4-6 membered partially orfully saturated heterocycle containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, where said lactone, saidlactam and said heterocycle are optionally substituted with one or moresubstituents; (iii) an amino group having attached thereto at least onechemical moiety selected from the group consisting of (C₁-C₈)alkyl,aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; or (iv) an (C₁-C₆)alkyl group having attached thereto atleast one chemical moiety selected from the group consisting of hydroxy,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylsulfamyl, di((C₁-C₃)alkyl)sulfamyl,acyloxy, a fully or partially saturated heterocycle, and a fully orpartially saturated carbocyclic ring, where said chemical moiety isoptionally substituted with one or more substituents; a pharmaceuticallyacceptable salt thereof, a prodrug of said compound or said salt.
 2. Thecompound of claim 1 wherein R⁴ is a group having Formula (IA)

where, R^(4b) and R^(4b′) are each independently hydrogen, H₂NC(O)—, ora chemical moiety selected from the group consisting of (C₁-C₆)alkyl,acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4b) or R^(4b′) taken together with R^(4e),R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, or anethylene bridge; X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, whereR^(4c) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4c) taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, oran ethylene bridge, and R^(4c′) is hydrogen, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a 3-6 membered partially or fully saturatedheterocycle, and a partially or fully saturated carbocyclic ring, wheresaid moiety is optionally substituted with one or more substituents, orR^(4c′) taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms abond, a methylene bridge, or an ethylene bridge; Y is oxygen, sulfur,—C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, and R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, a5-6 membered lactone ring, or a 4-6 membered lactam ring, where saidcarbocyclic ring, said heterocyclic ring, said lactone ring and saidlactam ring are optionally substituted with one or more substituents andsaid lactone ring and said lactam ring optionally contain an additionalheteroatom selected from oxygen, nitrogen or sulfur, or Y is —NR^(4d″)—,where R^(4d″) is a hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂—, or C(R^(4e))(R^(4e′)), where R^(4e) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, or R^(4e) takentogether with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4e′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4e′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge, or an ethylenebridge; and R^(4f) and R^(4f′) are each independently hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4f) or R^(4f′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, or anethylene bridge; a pharmaceutically acceptable salt thereof.
 3. Thecompound of claim of 2 wherein R⁰ and R¹ are each independently asubstituted phenyl; R^(4b) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′)forms a bond, a methylene bridge, or an ethylene bridge; R^(4b′) ishydrogen, an optionally substituted (C₁-C₃)alkyl, or taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, oran ethylene bridge; R^(4f′) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′)forms a bond, a methylene bridge, or an ethylene bridge; and R^(4f′) ishydrogen, an optionally substituted (C₁-C₃)alkyl, or taken together withR^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, oran ethylene bridge; a pharmaceutically acceptable salt thereof.
 4. Thecompound of claim 3 wherein X is —C(R^(4c))(R^(4c′))—, where R^(4c) andR^(4c′) are each independently hydrogen, H₂NC(O)—, or a chemical moietyselected from (C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or((C₁-C₄)alkyl)₂N—C(O)—, where said moiety is optionally substituted withone or more substituents, or either R^(4c) or R^(4c′) taken togetherwith R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylenebridge or an ethylene bridge; Y is —NR^(4d″)—, where R^(4d″) is ahydrogen or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl,(C₁-C₃)alkylaminosulfonyl, di(C₁-C₃)alkylaminosulfonyl, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is—C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are each independentlyhydrogen, H₂NC(O)—, or a chemical moiety selected from (C₁-C₆)alkyl,(C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, where said moiety isoptionally substituted with one or more substituents, or either R^(4e)or R^(4e′) taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′) formsa bond, a methylene bridge or an ethylene bridge; a pharmaceuticallyacceptable salt thereof.
 5. The compound of claim 4 wherein R^(4d″) is ahydrogen or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, (C₁-C₆)alkyl-O—C(O)—, and heteroaryl,where said moiety is optionally substituted with one or moresubstituents; a pharmaceutically acceptable salt thereof.
 6. Thecompound of claim 5 wherein R^(4d″) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl,(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, and (C₁-C₆)alkyl-O—C(O)—, where saidmoiety is optionally substituted with 1-3 fluorines, or R^(4d″) is aheteroaryl, where said heteroaryl is optionally substituted with 1 to 2substituents independently selected from the group consisting of chloro,fluoro, (C₁-C₃)alkoxy, (C₁-C₃)alkyl, and fluoro-substituted(C₁-C₃)alkyl; a pharmaceutically acceptable salt thereof.
 7. Thecompound of claims 4, 5 or 6 wherein R⁰ and R¹ are each independently aphenyl substituted with 1 to 3 substituents independently selected fromthe group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, and cyano; a pharmaceutically acceptablesalt thereof.
 8. The compound of claim 7 wherein R⁰ and R¹ are eachindependently a phenyl substituted with 1 to 2 substituentsindependently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; a pharmaceutically acceptable salt thereof.
 9. The compound ofclaim 8 wherein R⁰ is 2-chlorophenyl, 2-fluorophenyl,2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or2,4-difluorophenyl; and R¹ is 4-chlorophenyl or 4-fluorophenyl; apharmaceutically acceptable salt thereof.
 10. The compound of claim 9that is3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-methylpiperazin-1-yl)-2H-pyrazolo[3,4-c]pyridine;or a pharmaceutically acceptable salt thereof.
 11. The compound of claim3 wherein Y is —C(R^(4d))(R^(4d′))—, where R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, a5-6 membered lactone ring, or a 4-6 membered lactam ring, where saidcarbocyclic ring, said heterocyclic ring, said lactone ring and saidlactam ring are optionally substituted with one or more substituents andsaid lactone ring and said lactam ring optionally contain an additionalheteroatom selected from oxygen, nitrogen or sulfur; a pharmaceuticallyacceptable salt thereof.
 12. The compound of claim 11 wherein R^(4d) isamino, (C₁-C₆)alkylamino, di(C₁-C₄)alkylamino, azetidinyl, piperidinyl,pyrrolidinyl, morpholinyl, (C₃-C₆)cycloalkylamino, acylamino,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, piperidinyl,pyrrolidinyl, or morpholinyl; and R^(4d′) is (C₁-C₆)alkyl, H₂NC(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, or aryl; apharmaceutically acceptable salt thereof.
 13. The compound of claim 12wherein R^(4d) is amino, (C₁-C₆)alkylamino, di(C₁-C₄)alkylamino, or(C₃-C₆)cycloalkylamino; and R^(4d′) is H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—,or ((C₁-C₄)alkyl)₂N—C(O)—; a pharmaceutically acceptable salt thereof.14. The compound of claims 11, 12, or 13 wherein R⁰ and R¹ are eachindependently a phenyl substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof.
 15. The compound of claim 14wherein R⁰ and R¹ are each independently a phenyl substituted with 1 to2 substituents independently selected from the group consisting ofchloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted(C₁-C₄)alkyl), and cyano; a pharmaceutically acceptable salt thereof.16. The compound of claim 15 wherein R⁰ is 2-chlorophenyl,2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, or 2,4-difluorophenyl; and R¹ is 4-chlorophenylor 4-fluorophenyl; a pharmaceutically acceptable salt thereof.
 17. Thecompound of claim 16 selected from the group consisting of1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide;1′-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-isopropylaminopiperidine-4-carboxylicacid amide; and1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-3-ethylaminoazetidine-3-carboxylicacid amide; or a pharmaceutically acceptable salt thereof. 18.(canceled)
 19. The compound of claim 11 wherein R^(4d) is hydrogen,hydroxy, amino, cyano or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₆)alkylamino-, and di(C₁-C₄)alkylamino-,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, where said moiety isoptionally substituted with one or more substituents; and R^(4d′) ishydrogen, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, aryl and heteroaryl, where said moiety is optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof.
 20. The compound of claim 19 wherein X is a bond or—C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are each independentlyhydrogen or an optionally substituted (C₁-C₆)alkyl, or either R^(4c) orR^(4c′) taken together with R^(4e) or R^(4e′) forms a bond, a methylenebridge or an ethylene bridge; and Z is a bond or —C(R^(4e))(R^(4e′))—,where R^(4e) and R^(4e′) are each independently hydrogen or anoptionally substituted (C₁-C₆)alkyl, or either R^(4e) or R^(4e′) takentogether with R^(4c) or R^(4c′) forms a bond, a methylene bridge or anethylene bridge; a pharmaceutically acceptable salt thereof.
 21. Thecompound of claim 20 wherein R^(4c) and R^(4c′) are each hydrogen oreither R^(4c) or R^(4c′) taken together with R^(4e) or R^(4e′) forms abond; R^(4d) is hydrogen, hydroxy, amino, cyano, or a chemical moietyselected from the group consisting of (C₁-C₆)alkoxy, acyl,(C₁-C₆)alkylamino-, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, anddi(C₁-C₄)alkylamino-; R^(4d′) is hydrogen, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl and aryl, where said moiety isoptionally substituted with one or more substituents; and R^(4e) andR^(4e′) are hydrogen or either R^(4e) or R^(4e′) taken together withR^(4c) or R^(4c′) forms a bond; a pharmaceutically acceptable saltthereof.
 22. The compound of claims 19, 20, or 21 wherein R⁰ and R¹ areeach independently a phenyl substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof.
 23. The compound of claim 22wherein R⁰ and R¹ are each independently a phenyl substituted with 1 to2 substituents independently selected from the group consisting ofchloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted(C₁-C₄)alkyl), and cyano; a pharmaceutically acceptable salt thereof.24. The compound of claim 23 wherein R⁰ is 2-chlorophenyl,2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, or 2,4-difluorophenyl; and R¹ is 4-chlorophenylor 4-fluorophenyl; a pharmaceutically acceptable salt thereof. 25.(canceled)
 26. The compound of claim 11 wherein R^(4b), R^(4b′), R^(4f),and R^(4f′) are all hydrogen; and R^(4d) and R^(4d′) taken together forma 3-6 membered partially or fully saturated carbocyclic ring, a 3-6membered partially or fully saturated heterocyclic ring, a 5-6 memberedlactone ring, or a 4-6 membered lactam ring, where said carbocyclicring, said heterocyclic ring, said lactone ring and said lactam ring areoptionally substituted with one or more substituents and said lactonering or said lactam ring optionally contains an additional heteroatomselected from oxygen, nitrogen or sulfur; a pharmaceutically acceptablesalt thereof.
 27. The compound of claim 26 wherein X is a bond, —CH₂CH₂—or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′), are eachindependently hydrogen or an optionally substituted (C₁-C₆)alkyl, oreither R^(4c) or R^(4c′) taken together with R^(4e) or R^(4e′) forms abond, a methylene bridge or an ethylene bridge; and Z is a bond,—CH₂CH₂— or —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are eachindependently hydrogen or an optionally substituted (C₁-C₆)alkyl, oreither R^(4e) or R^(4e′) taken together with R^(4c) or R^(4c′) forms abond, a methylene bridge or an ethylene bridge; a pharmaceuticallyacceptable salt thereof.
 28. The compound of claim 27 wherein R^(4d) andR^(4d′) taken together form a 3-6 membered partially or fully saturatedcarbocyclic ring, a 3-6 membered partially or fully saturatedheterocyclic ring, or a 5-6 membered lactam ring, where said lactam ringis optionally substituted with one or more substituents and optionallycontains an additional heteroatom selected from nitrogen or oxygen; apharmaceutically acceptable salt thereof.
 29. The compound of claim 28wherein X is a bond or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′)are each hydrogen; and Z is a bond or C(R^(4e))(R^(4e′))—, where R^(4e)and R^(4e′) are each hydrogen; a pharmaceutically acceptable saltthereof.
 30. The compound of claims 26, 27, 28 or 29 wherein R⁰ and R¹are each independently a phenyl substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof.
 31. The compound of claim 30wherein R⁰ and R¹ are each independently a phenyl substituted with 1 to2 substituents independently selected from the group consisting ofchloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted(C₁-C₄)alkyl), and cyano; a pharmaceutically acceptable salt thereof.32. The compound of claim 31 wherein R⁰ is 2-chlorophenyl,2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, or 2,4-difluorophenyl; and R¹ is 4-chlorophenylor 4-fluorophenyl; a pharmaceutically acceptable salt thereof. 33.(canceled)
 34. The compound of claim 1 wherein R⁴ is a group of Formula(IB)

where R^(4a) is as defined in claim 1; R^(4b) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, R^(4b′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4b) or R^(4b′) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) is hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4c) taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, oran ethylene bridge, and R^(4c′) is hydrogen, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a 3-6 membered partially or fully saturatedheterocycle, and a partially or fully saturated carbocyclic ring, wheresaid moiety is optionally substituted with one or more substituents, orR^(4c′) taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms abond, a methylene bridge, or an ethylene bridge; Y is oxygen, sulfur,—C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, and R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, a5-6 membered lactone ring, or a 4-6 membered lactam ring, where saidcarbocyclic ring, said heterocyclic ring, said lactone ring and saidlactam ring are optionally substituted with one or more substituents andsaid lactone ring and said lactam ring optionally contain an additionalheteroatom selected from oxygen, nitrogen or sulfur; Y is —NR^(4d″)—,where R^(4d″) is a hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂—, or C(R^(4e))(R^(4e′)), where R^(4e) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocyclicring, and a partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, orR^(4e) taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms abond, a methylene bridge, or an ethylene bridge, and R^(4e′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4e′) taken togetherwith R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylenebridge, or an ethylene bridge; R^(4f) is hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents; and R^(4f′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4f) or R^(4f′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, or anethylene bridge; a pharmaceutically acceptable salt thereof.
 35. Thecompound of claim 34 wherein R⁰ and R¹ are each independently asubstituted phenyl; R^(4a), R^(4b), R^(4b′), R^(4f) and R^(4f′) are eachhydrogen; a pharmaceutically acceptable salt thereof.
 36. The compoundof claim 35 wherein X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, whereR^(4c) and R^(4c′) are each independently hydrogen or (C₁-C₆)alkyl; Y is—NR^(4d″)—, where R^(4d″) is hydrogen or a chemical moiety selected fromthe group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; Z is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))-, whereR^(4c) and R^(4c′) are each independently hydrogen or (C₁-C₆)alkyl; apharmaceutically acceptable salt thereof.
 37. The compound of claim 35or 36 wherein R⁰ and R¹ are each independently a phenyl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, andcyano; a pharmaceutically acceptable salt thereof.
 38. The compound ofclaim 37 wherein R⁰ and R¹ are each independently a phenyl substitutedwith 1 to 2 substituents independently selected from the groupconsisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano; a pharmaceuticallyacceptable salt thereof.
 39. The compound of claim 38 wherein R⁰ is2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or 2,4-difluorophenyl;and R¹ is 4-chlorophenyl or 4-fluorophenyl; a pharmaceuticallyacceptable salt thereof.
 40. (canceled)
 41. The compound of claim 1wherein R⁴ is a group of Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl, or (C₁-C₄)alkyl,and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or an optionallysubstituted 4-6 membered partially or fully saturated heterocylic ringcontaining 1 to 2 heteroatoms independently selected from oxygen, sulfuror nitrogen, or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6membered lactone, 4-6 membered lactam, or a 4-6 membered partially orfully saturated heterocycle containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, where said lactone, saidlactam and said heterocycle are optionally substituted with one or moresubstituents; a pharmaceutically acceptable salt thereof.
 42. Thecompound of claim 41 wherein R⁰ and R¹ are each independently asubstituted phenyl; a pharmaceutically acceptable salt thereof.
 43. Thecompound of claim 41 or 42 wherein R⁰ and R¹ are each independently aphenyl substituted with 1 to 3 substituents independently selected fromthe group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, and cyano; a pharmaceutically acceptablesalt thereof.
 44. The compound of claim 43 wherein R⁰ and R¹ are eachindependently a phenyl substituted with 1 to 2 substituentsindependently selected from the group consisting of bromo, chloro,fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl),and cyano; a pharmaceutically acceptable salt thereof.
 45. (canceled)46. The compound of claim 44 wherein R⁰ is 2-chlorophenyl,2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, or 2,4-difluorophenyl; and R¹ is 4-chlorophenylor 4-fluorophenyl; a pharmaceutically acceptable salt thereof. 47.(canceled)
 48. The compound of claim 1 wherein R⁴ is an amino grouphaving attached thereto at least one chemical moiety selected from thegroup consisting of (C₁-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl, a 3-8 memberedpartially or fully saturated carbocyclic ring, hydroxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, heteroaryl(C₁-C₃)alkyl, and a fully orpartially saturated heterocycle, where said chemical moiety isoptionally substituted with one or more substituents; a pharmaceuticallyacceptable salt thereof.
 49. The compound of claim 48 wherein R⁰ and R¹are each independently a substituted phenyl; a pharmaceuticallyacceptable salt thereof.
 50. The compound of claim 48 or 49 wherein R⁰and R¹ are each independently a phenyl substituted with 1 to 3substituents independently selected from the group consisting of halo,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof.
 51. The compound of claim 50wherein R⁰ and R¹ are each independently a phenyl substituted with 1 to2 substituents independently selected from the group consisting ofchloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted(C₁-C₄)alkyl, and cyano; a pharmaceutically acceptable salt thereof. 52.The compound of claim 51 wherein R⁰ is 2-chlorophenyl, 2-fluorophenyl,2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or2,4-difluorophenyl; and R¹ is 4-chlorophenyl or 4-fluorophenyl; apharmaceutically acceptable salt thereof.
 53. The compound of claim 52that is3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[3,4-c]pyridine;a pharmaceutically acceptable salt thereof.
 54. (canceled)
 55. Acompound of Formula (I)

wherein A is C(R²), where R² is hydrogen, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl, or (C₁-C₄)alkoxy, R^(0a), R^(0b), R^(1a), and R^(1b) areeach independently halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl, or cyano; n and m are each independently 0, 1 or 2; R³ ishydrogen, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or (C₁-C₄)alkoxy;R⁴ is (i) a group having Formula (IA) or Formula (IB)

where R^(4a) is hydrogen or (C₁-C₃)alkyl; R^(4b) and R^(4b′) are eachindependently hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents, or either R^(4b) or R^(4b′)taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are each independentlyhydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda 3-6 membered partially or fully saturated carbocyclic ring, where themoiety is optionally substituted with one or more substituents, oreither R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge or an ethylene bridge; Y isoxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) andR^(4d′) are each independently hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents, or R^(4d) andR^(4d′) taken together form a 3-6 membered partially or fully saturatedcarbocyclic ring, a 3-6 membered partially or fully saturatedheterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactamring, where said carbocyclic ring, said heterocyclic ring, said lactonering and said lactam ring are optionally substituted with one or moresubstituents and said lactone ring and said lactam ring optionallycontain an additional heteroatom selected from oxygen, nitrogen orsulfur, or Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted with one or moresubstituents; Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, whereR^(4e) and R^(4e′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocyclic ring, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents, or eitherR^(4e) or R^(4e′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; andR^(4f) and R^(4f′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents, or eitherR^(4f) or R^(4f′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; (ii) agroup having Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl, or (C₁-C₄)alkyl,and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or an optionallysubstituted 4-6 membered partially or fully saturated heterocylic ringcontaining 1 to 2 heteroatoms independently selected from oxygen, sulfuror nitrogen, or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6membered lactone, 4-6 membered lactam, or a 4-6 membered partially orfully saturated heterocycle containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, where said lactone, saidlactam and said heterocycle are optionally substituted with one or moresubstituents; (iii) an amino group having attached thereto at least onechemical moiety selected from the group consisting of (C₁-C₈)alkyl,aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; or (iv) an (C₁-C₆)alkyl group having attached thereto atleast one chemical moiety selected from the group consisting of hydroxy,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylsulfamyl, di((C₁-C₃)alkyl)sulfamyl,acyloxy, a fully or partially saturated heterocycle, and a fully orpartially saturated carbocyclic ring, where said chemical moiety isoptionally substituted with one or more substituents; a pharmaceuticallyacceptable salt thereof.
 56. The compound of claim 55 wherein R⁴ is agroup of Formula (IA);

where, R^(4b) and R^(4b′) are each independently hydrogen, H₂NC(O)—, ora chemical moiety selected from the group consisting of (C₁-C₆)alkyl,acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturatedheterocycle, and a 3-6 membered partially or fully saturated carbocyclicring, where said moiety is optionally substituted with one or moresubstituents, or R^(4b) or R^(4b′) taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an ethylenebridge; X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))-, where R^(4c) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, or R^(4c) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4c′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4c′) taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an ethylenebridge; Y is oxygen, sulfur, —C(O)—, or C(R^(4d))(R^(4d′))—, whereR^(4d) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, and, R^(4d′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4d) and R^(4d′) taken together form a 3-6membered partially or fully saturated carbocyclic ring, a 3-6 memberedpartially or fully saturated heterocyclic ring, a 5-6 membered lactonering, or a 4-6 membered lactam ring, where said carbocyclic ring, saidheterocyclic ring, said lactone ring and said lactam ring are optionallysubstituted with one or more substituents and said lactone ring and saidlactam ring optionally contain an additional heteroatom selected fromoxygen, nitrogen or sulfur, or Y is —NR^(4d″), where R^(4d″) is ahydrogen or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂—, or C(R^(4e))(R^(4e′)), where R^(4e) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, or R^(4e) takentogether with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4e′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4e′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge, or an ethylenebridge; and R^(4f) and R^(4f′) are each independently hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4f) or R^(4f′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, or anethylene bridge; a pharmaceutically acceptable salt thereof.
 57. Thecompound of claim of 56 wherein R^(4b) is hydrogen, an optionallysubstituted (C₁-C₃)alkyl, or taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an ethylenebridge; R^(4b′) is hydrogen, an optionally substituted (C₁-C₃)alkyl, ortaken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; R^(4f) is hydrogen, anoptionally substituted (C₁-C₃)alkyl, or taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, or anethylene bridge; and R^(4f′) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′)forms a bond, a methylene bridge, or an ethylene bridge; apharmaceutically acceptable salt thereof.
 58. The compound of claim 57wherein X is —C(R^(4c)(R^(4c′))—, where R^(4c) and R^(4c′) are eachindependently hydrogen, H₂NC(O)—, or a chemical moiety selected from(C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, wheresaid moiety is optionally substituted with one or more substituents, oreither R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′) R^(4f), orR^(4f′) forms a bond, a methylene bridge or an ethylene bridge; Y is—NR^(4d″)—, where R^(4d″) is a hydrogen or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; Z is —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) areeach independently hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom (C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—,where said moiety is optionally substituted with one or moresubstituents, or either R^(4e) or R^(4e′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge or anethylene bridge; a pharmaceutically acceptable salt thereof.
 59. Thecompound of claim 58 wherein R^(4d″) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₃)alkylsulfonyl,(C₁-C₃)alkylaminosulfonyl, di(C₁-C₃)alkylaminosulfonyl, acyl,(C₁-C₆)alkyl-O—C(O)—, and heteroaryl, where said moiety is optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof.
 60. The compound of claim 59 wherein R^(4d″) is a hydrogenor a chemical moiety selected from the group consisting of(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, and (C₁-C₆)alkyl-O—C(O)—, where saidmoiety is optionally substituted with 1-3 fluorines, or R^(4d″) is aheteroaryl, where said heteroaryl is optionally substituted with 1 to 2substituents independently selected from the group consisting of chloro,fluoro, (C₁-C₃)alkoxy, (C₁-C₃)alkyl, and fluoro-substituted(C₁-C₃)alkyl; a pharmaceutically acceptable salt thereof.
 61. Thecompound of claims 58, 59, or 60 wherein R^(0a), R^(0a), R^(1a) andR^(1b) are each independently selected from the group consisting ofhalo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, andcyano; a pharmaceutically acceptable salt thereof.
 62. The compound ofclaim 61 wherein R^(0a), R^(0a), R^(1a) and R^(1b) are eachindependently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; and n and m are each independently 0 or 1; a pharmaceuticallyacceptable salt thereof, a prodrug of said compound or said salt. 63.The compound of claim 57 wherein Y is —C(R^(4d))(R^(4d′))—, where R^(4d)is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy,acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-,(C₃-C₆)cycloalkylamino-, acylamino-, aryl(C₁-C₄)alkylamino-,heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partiallyor fully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, R^(4d′) is hydrogen, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a 3-6 membered partially or fully saturatedheterocycle, and a partially or fully saturated carbocyclic ring, wheresaid moiety is optionally substituted with one or more substituents, orR^(4d) and R^(4d′) taken together form a 3-6 membered partially or fullysaturated carbocyclic ring, a 3-6 membered partially or fully saturatedheterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactamring, where said carbocyclic ring, said heterocyclic ring, said lactonering and said lactam ring are optionally substituted with one or moresubstituents and said lactone ring and said lactam ring optionallycontain an additional heteroatom selected from oxygen, nitrogen orsulfur; a pharmaceutically acceptable salt thereof.
 64. The compound ofclaim 63 wherein R^(4b), R^(4b′), R^(4f), and R^(4f′) are all hydrogen;R^(4d) is amino, (C₁-C₆)alkylamino, di(C₁-C₄)alkylamino,(C₃-C₆)cycloalkylamino, acylamino, aryl(C₁-C₄)alkylamino-,heteroaryl(C₁-C₄)alkylamino-; and R^(4d′) is (C₁-C₆)alkyl, H₂NC(O)—,(C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, or aryl; apharmaceutically acceptable salt thereof.
 65. The compound of claim 64wherein X is a bond or C(R^(4c))(R^(4c′))-, where R^(4c) and R^(4c′) areeach hydrogen; and Z is a bond or C(R^(4e))(R^(4e′))—, where R^(4e) andR^(4e′) are each hydrogen; a pharmaceutically acceptable salt thereof.66. The compound of claim 65 wherein R^(4d) is amino, (C₁-C₆)alkylamino,di(C₁-C₄)alkylamino, (C₃-C₆)cycloalkylamino; and R^(4d′) is H₂NC(O)—,(C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—; a pharmaceuticallyacceptable salt thereof.
 67. The compound of claims 63, 64, 65 or 66wherein R^(0a), R^(0b), R^(1a), and R^(1b) are each independentlyselected from the group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, and cyano; a pharmaceutically acceptablesalt thereof.
 68. The compound of claim 67 wherein R^(0a), R^(0b),R^(1a), and R^(1b) are each independently selected from the groupconsisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano; and n and m are eachindependently selected from 0 or 1; a pharmaceutically acceptable saltthereof.
 69. The compound of claim 63 wherein R^(4b), R^(4b′), R^(4f),and R^(4f′) are all hydrogen; R^(4d) is hydrogen, hydroxy, amino, or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₆)alkylamino-,and di(C₁-C₄)alkylamino-, where said moiety is optionally substitutedwith one or more substituents; and R^(4d′) is hydrogen, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, aryl andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; a pharmaceutically acceptable salt thereof.
 70. Thecompound of claim 69 wherein X is a bond or —C(R^(4c))(R^(4c′))—, whereR^(4c) and R^(4c′) are each independently hydrogen or an optionallysubstituted (C₁-C₆)alkyl, or either R^(4c) or R^(4c′) taken togetherwith R^(4e) or R^(4e′) forms a bond, a methylene bridge or an ethylenebridge; and Z is a bond or —C(R^(4e))(R^(4e′))—, where R^(4e) andR^(4e′) are each independently hydrogen or an optionally substituted(C₁-C₆)alkyl, or either R^(4e) or R^(4e′) taken together with R^(4c) orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; apharmaceutically acceptable salt thereof.
 71. The compound of claim 70wherein R^(4c) and R^(4c′) are each hydrogen or either R^(4c) or R^(4c′)taken together with R^(4e) or R^(4e′) forms a bond; R^(4d) is hydrogen,hydroxy, amino, or a chemical moiety selected from the group consistingof (C₁-C₆)alkoxy, acyl, (C₁-C₆)alkylamino-, and di(C₁-C₄)alkylamino-;R^(4d′) is hydrogen, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl and aryl, where said moiety is optionallysubstituted with one or more substituents; and R^(4e) and R^(4e′) arehydrogen or either R^(4e) or R^(4e′) taken together with R^(4c) orR^(4c′) forms a bond; a pharmaceutically acceptable salt thereof. 72.The compound of claims 69, 70, or 71 wherein R^(0a), R^(0b), R^(1a), andR^(1b) are each independently selected from the group consisting ofhalo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, andcyano; a pharmaceutically acceptable salt thereof.
 73. The compound ofclaim 72 wherein R^(0a), R^(0b), R^(1a), and R^(1b) are eachindependently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; and n and m are each independently 0 or 1; a pharmaceuticallyacceptable salt thereof.
 74. The compound of claim 63 wherein R^(4b),R^(4b′), R^(4f), and R^(4f′) are all hydrogen; and R^(4d) and R^(4d′)taken together form a 3-6 membered partially or fully saturatedcarbocyclic ring, a 3-6 membered partially or fully saturatedheterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactamring, where said carbocyclic ring, said heterocyclic ring, said lactonering and said lactam ring are optionally substituted with one or moresubstituents and said lactone ring or said lactam ring optionallycontains an additional heteroatom selected from oxygen, nitrogen orsulfur; a pharmaceutically acceptable salt thereof.
 75. The compound ofclaim 74 wherein X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, whereR^(4c) and R^(4c′) are each independently hydrogen or an optionallysubstituted (C₁-C₆)alkyl, or either R^(4c) or R^(4c′) taken togetherwith R^(4e) or R^(4e′) forms a bond, a methylene bridge or an ethylenebridge; and Z is a bond, —CH₂CH₂— or —C(R^(4e))(R^(4e′))—, where R^(4e)and R^(4e′) are each independently hydrogen or an optionally substituted(C₁-C₆)alkyl, or either R^(4e) or R^(4e′) taken together with R^(4c) orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; apharmaceutically acceptable salt thereof.
 76. The compound of claim 75wherein R^(4d) and R^(4d′) taken together form a 5-6 membered lactamring, where said lactam ring is optionally substituted with one or moresubstituents and optionally contains an additional heteroatom selectedfrom nitrogen or oxygen; a pharmaceutically acceptable salt thereof. 77.The compound of claim 76 wherein X is a bond or —C(R^(4c))(R^(4c′))—,where R^(4c) and R^(4c′) are each hydrogen; and Z is a bond orC(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are each hydrogen; apharmaceutically acceptable salt thereof.
 78. The compound of claims 74,75, 76 or 77 wherein R^(0a), R^(0b), R^(1a), and R^(1b) are eachindependently selected from the group consisting of halo, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof.
 79. The compound of claim 78wherein R^(0a), R^(0b), R^(1a), and R^(1b) are each independentlyselected from the group consisting of chloro, fluoro, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), and cyano; n and m areeach independently 0 or 1; a pharmaceutically acceptable salt thereof.80. The compound of claim 55 wherein R⁴ is a group of Formula (IB);

where R^(4a) is as defined in claim 43; R^(4b) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, R^(4b′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4b) or R^(4b′) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) is hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4c) taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, oran ethylene bridge, and R^(4c′) is hydrogen, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a 3-6 membered partially or fully saturatedheterocycle, and a partially or fully saturated carbocyclic ring, wheresaid moiety is optionally substituted with one or more substituents, orR^(4c′) taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms abond, a methylene bridge, or an ethylene bridge; Y is oxygen, sulfur,—C(O)—, or —C(R^(4d))(R^(4d′)), where R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, and R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, a5-6 membered lactone ring, or a 4-6 membered lactam ring, where saidcarbocyclic ring, said heterocyclic ring, said lactone ring and saidlactam ring are optionally substituted with one or more substituents andsaid lactone ring and said lactam ring optionally contain an additionalheteroatom selected from oxygen, nitrogen or sulfur; Y is —NR^(4d″)—,where R^(4d″) is a hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, or R^(4e) takentogether with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4e′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4e′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge, or an ethylenebridge; R^(4f) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂-amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents; and R^(4f′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4f) or R^(4f′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, or anethylene bridge; a pharmaceutically acceptable salt thereof.
 81. Thecompound of claim 80 wherein R^(4a), R^(4b), R^(4b′), R^(4f) and R^(4f′)are each hydrogen; a pharmaceutically acceptable salt thereof.
 82. Thecompound of claim 81 wherein X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R⁴ and R^(4c′) are each independentlyhydrogen or (C₁-C₆)alkyl; Y is —NR^(4d″)—, where R^(4d″) is hydrogen ora chemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; Z is a bond, —CH₂CH₂— or —C(R^(4c)(R^(4c′))—, where R^(4c)and R^(4c′) are each independently hydrogen or (C₁-C₆)alkyl; apharmaceutically acceptable salt thereof.
 83. The compound of claims 81or 82 wherein R_(0a), R^(0b), R^(1a) and R^(1b) are each independentlyselected from the group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, and cyano; a pharmaceutically acceptablesalt thereof.
 84. The compound of claim 83 wherein R^(0a), R^(0b),R^(1a) and R^(1b) are each independently selected from the groupconsisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano; and n and m are eachindependently 0 or 1; a pharmaceutically acceptable salt thereof. 85.The compound of claim 55 wherein R⁴ is a group having Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl or (C₁-C₄)alkyl,and R⁷ is (C₁-C₄)alkyl-, halo-substituted (C₁-C₄)alkyl-,(C₁-C₄)alkoxy(C₁-C₄)alkyl-, (C₁-C₄)alkylamino(C₁-C₄)alkyl-,di(C₁-C₄)alkylamino(C₁-C₄)alkyl-, or a 4-6 membered partially or fullysaturated heterocylic ring containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, or R⁵ and R⁶, or R⁵ and R⁷taken together form a 5-6 membered lactone, 4-6 membered lactam, or a4-6 membered partially or fully saturated heterocycle containing 1 to 2heteroatoms independently selected from oxygen, sulfur or nitrogen,where said lactone, said lactam and said heterocycle are optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof.
 86. The compound of claim 85 wherein n and m are eachindependently 1 or 0; a pharmaceutically acceptable salt thereof. 87.The compound of claim 86 wherein R⁵ and R⁶ are each independentlyhydrogen or (C₁-C₄)alkyl, and R⁷ is (C₁-C₄)alkyl; a pharmaceuticallyacceptable salt thereof.
 88. The compound of claims 86 or 87 whereinR^(0a), R^(0b), R^(1a), and R^(1b) are each independently chloro, fluoroor trifluoromethyl; a pharmaceutically acceptable salt thereof.
 89. Thecompound of claim 55 wherein R⁴ is an amino group having attachedthereto at least one chemical moiety selected from the group consistingof (C₁-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially orfully saturated carbocyclic ring, hydroxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, heteroaryl(C₁-C₃)alkyl, and a partially orfully saturated heterocycle, where said chemical moiety is optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof.
 90. The compound of claim 89 wherein n and m are eachindependently 1 or 0; a pharmaceutically acceptable salt thereof. 91.The compound of claims 89 or 90 wherein R^(0a), R^(0b), R^(1a), andR^(1b) are each independently chloro, fluoro or trifluoromethyl; apharmaceutically acceptable salt thereof.
 92. The compound of claim 55wherein R⁴ is an (C₁-C₆)alkyl group having attached thereto at least onechemical moiety selected from the group consisting of hydroxy,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylsulfamyl, di((C₁-C₃)alkyl)sulfamyl,acyloxy, a partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said chemical moiety isoptionally substituted with one or more substituents; a pharmaceuticallyacceptable salt thereof.
 93. The compound of claim 92 wherein n and mare each independently 1 or 0; a pharmaceutically acceptable saltthereof.
 94. The compound of claims 92 or 93 wherein R^(0a), R^(0b),R^(1a), and R^(1b) are each independently chloro, fluoro ortrifluoromethyl; a pharmaceutically acceptable salt thereof.
 95. Apharmaceutical composition comprising (1) a compound of claim 1 and (2)a pharmaceutically acceptable excipient, diluent, or carrier.
 96. Thecomposition of claim 95 further comprising at least one additionalpharmaceutical agent.
 97. The composition of claim 96 wherein saidadditional pharmaceutical agent is a nicotine receptor partial agonist,an opioid antagonist, a dopaminergic agent, an attention deficitdisorder agent, or an anti-obesity agent.
 98. The composition of claim97 wherein said anti-obesity agent is selected from the group consistingof an apo-B/MTP inhibitor, a 11β-hydroxy steroid dehydrogenase-1inhibitor, peptide YY₃₋₃₆, a MCR-4 agonist, a CCK-A agonist, a monoaminereuptake inhibitor, a sympathomimetic agent, a 3 adrenergic receptoragonist, a dopamine agonist, a melanocyte-stimulating hormone receptor,a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist,leptin, a leptin receptor agonist, a galanin antagonist, a lipaseinhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, athyromimetic agent, dehydroepiandrosterone, a glucocorticoid receptorantagonist, an orexin receptor antagonist, a glucagon-like peptide-1receptor agonist, a ciliary neurotrophic factor, a human agouti-relatedprotein antagonist, a ghrelin receptor antagonist, a histamine 3receptor antagonist or inverse agonist, and a neuromedin U receptoragonist.
 99. A method for treating obesity, bulimia, depression, bipolardisorders, psychoses, schizophrenia, alcoholism, tobacco abuse,dementia, epilepsy, attention deficit disorder, Parkinson's disease,inflammation, and type II diabetes in animals comprising the step ofadministering to an animal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1; a pharmaceutically acceptablesalt thereof.
 100. The method of claim 99 wherein said compound is acompound of claim 2, a pharmaceutically acceptable salt thereof. 101.The method of claim 99 wherein said compound is administered incombination with a nicotine receptor partial agonist, an opioidantagonist, a dopaminergic agent, an attention deficit disorder agent,or an anti-obesity agent.
 102. The method of claim 100 wherein saidcompound is administered in combination with a nicotine receptor partialagonist, an opioid antagonist, a dopaminergic agent, an attentiondeficit disorder agent, or an anti-obesity agent.
 103. The method ofclaims 101 or 102 wherein said anti-obesity agent is selected from thegroup consisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroiddehydrogenase-1 inhibitor, peptide YY₃₋₃₆, a MCR-4 agonist, a CCK-Aagonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a 3adrenergic receptor agonist, a dopamine agonist, amelanocyte-stimulating hormone receptor, a 5-HT2c receptor agonist, amelanin concentrating hormone antagonist, leptin, a leptin receptoragonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, aneuropeptide-Y receptor antagonist, a thyromimetic agent,dehydroepiandrosterone, a glucocorticoid receptor antagonist, an orexinreceptor antagonist, a glucagon-like peptide-1 receptor agonist, aciliary neurotrophic factor, a human agouti-related protein antagonist,a ghrelin receptor antagonist, a histamine 3 receptor antagonist orinverse agonist, and a neuromedin U receptor agonist.
 104. (canceled)105. The method of claim 99 wherein said disease, condition or disorderis obesity, bulimia, attention deficit disorder, Parkinson's disease,dementia, alcoholism, or tobacco abuse.
 106. A method for treatingobesity, bulimia, depression, bipolar disorders, psychoses,schizophrenia, alcoholism, tobacco abuse, dementia, epilepsy, attentiondeficit disorder, Parkinson's disease, inflammation, and type IIdiabetes comprising the step of administering a pharmaceuticalcomposition of claim
 95. 107. The method of claim 106 wherein saidpharmaceutical composition further comprises an additionalpharmaceutical agent.
 108. The method of claim 107 wherein saidadditional pharmaceutical agent is a nicotine partial agonist, an opioidantagonist, a dopaminergic agent, an attention deficit disorder agent,or an anti-obesity agent.
 109. The method of claim 108 wherein saidanti-obesity agent is selected from the group consisting of an apo-B/MTPinhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptideYY₃₋₃₆, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptakeinhibitor, a sympathomimetic agent, a β₃ adrenergic receptor agonist, adopamine agonist, a melanocyte-stimulating hormone receptor, a 5-HT2creceptor agonist, a melanin concentrating hormone antagonist, leptin, aleptin receptor agonist, a galanin antagonist, a lipase inhibitor, abombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimeticagent, dehydroepiandrosterone, a glucocorticoid receptor antagonist, anorexin receptor antagonist, a glucagon-like peptide-1 receptor agonist,a ciliary neurotrophic factor, a human agouti-related proteinantagonist, a ghrelin receptor antagonist, a histamine 3 receptorantagonist or inverse agonist, and a neuromedin U receptor agonist. 110.The method of claims 106, 107, 108 or 109 wherein said disease,condition or disorder is obesity, bulimia, attention deficit disorder,Parkinson's disease, dementia, alcoholism, or tobacco abuse.
 111. Amethod for treating obesity, bulimia, depression, bipolar disorders,psychoses, schizophrenia, alcoholism, tobacco abuse, dementia, epilepsy,attention deficit disorder, Parkinson's disease, inflammation, and typeII diabetes in animals comprising the step of administering to an animalin need of such treatment a therapeutically effective amount of acompound of claim 55; or a pharmaceutically acceptable salt thereof.112. The method of claim 111 wherein said compound is a compound ofclaim 56, a pharmaceutically acceptable salt thereof.
 113. The method ofclaim 111 wherein said compound is administered in combination with anicotine partial agonist, an opioid antagonist, a dopaminergic agent, anattention deficit disorder agent, or an anti-obesity agent.
 114. Themethod of claim 112 wherein said compound is administered in combinationwith a nicotine partial agonist, an opioid antagonist, a dopaminergicagent, an attention deficit disorder agent, or an anti-obesity agent.115. The method of claim 113 or 114 wherein said anti-obesity agent isselected from the group consisting of an apo-B/MTP inhibitor, a11β-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY₃₋₃₆, a MCR-4agonist, a CCK-A agonist, a monoamine reuptake inhibitor, asympathomimetic agent, a 3 adrenergic receptor agonist, a dopamineagonist, a melanocyte-stimulating hormone receptor, a 5-HT2c receptoragonist, a melanin concentrating hormone antagonist, leptin, a leptinreceptor agonist, a galanin antagonist, a lipase inhibitor, a bombesinagonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent,dehydroepiandrosterone, a glucocorticoid receptor antagonist, an orexinreceptor antagonist, a glucagon-like peptide-1 receptor agonist, aciliary neurotrophic factor, a human agouti-related protein antagonist,a ghrelin receptor antagonist, a histamine 3 receptor antagonist orinverse agonist, and a neuromedin U receptor agonist.
 116. (canceled)117. The method of claim 111 wherein said disease, condition or disorderis obesity, bulimia, attention deficit disorder, Parkinson's disease,dementia, alcoholism, or tobacco abuse.
 118. A method for treating aobesity, bulimia, depression, bipolar disorders, psychoses,schizophrenia, alcoholism, tobacco abuse, dementia, epilepsy, attentiondeficit disorder, Parkinson's disease, inflammation, and type IIdiabetes in animals comprising the step of administering to an animal inneed of such treatment two separate pharmaceutical compositionscomprising (i) a first composition comprising a compound of claim 1 orclaim 55, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient, diluent, or carrier, and (ii) asecond composition comprising at least one additional pharmaceuticalagent and a pharmaceutically acceptable excipient, diluent, or carrier.119. The method of claim 118 wherein said at least one additionalpharmaceutical agent is a nicotine partial agonist, an opioidantagonist, a dopaminergic agent, an attention deficit disorder agent,or an anti-obesity agent.
 120. The method of claim 119 wherein saidanti-obesity agent is selected from the group consisting of an apo-B/MTPinhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptideYY₃₋₃₆, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptakeinhibitor, a sympathomimetic agent, a 3 adrenergic receptor agonist, adopamine agonist, a melanocyte-stimulating hormone receptor, a 5-HT2creceptor agonist, a melanin concentrating hormone antagonist, leptin, aleptin receptor agonist, a galanin antagonist, a lipase inhibitor, abombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimeticagent, dehydroepiandrosterone, a glucocorticoid receptor antagonist, anorexin receptor antagonist, a glucagon-like peptide-1 receptor agonist,a ciliary neurotrophic factor, a human agouti-related proteinantagonist, a ghrelin receptor antagonist, a histamine 3 receptorantagonist or inverse agonist, and a neuromedin U receptor agonist. 121.The method of claim 118 wherein said first composition and said secondcomposition are administered simultaneously.
 122. The method of claim118 wherein said first composition and said second composition areadministered sequentially and in any order.
 123. A compound of Formula(1c), (1d), (2e),

wherein R⁰, R¹, R², R³ are as defined in claim 1; R is an alkyl group;Pg is an amino-protecting group; and L is a leaving group.